NO146774B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PIPERAZINE AND PIPERIDE INGREDIENTS - Google Patents

Description

The present invention relates to analogue methods for the production of therapeutically active piperazine and piperidine derivatives with the general formula:

and pharmaceutically acceptable acid addition salts thereof, wherein:

Ar 1 and Ar 2 are each independently selected from phenyl, substituted phenyl and pyridinyl, wherein said substituted phenyl is phenyl with from 1-2 substituents independently selected from halogen, lower alkyl, lower alkoxy, trifluoromethyl and

nitro;

m is an integer equal to 0 or 1;

A is selected from ^N- and ^CH-, provided that when A is ^>N- so is

m zero and when A is -^CH- then m=l;

n is an integer from 2 to 6, provided that when <C>n<H>2n represents a branched alkylene chain, then at least 2 C atoms are present in the linear portion of the chain connecting B

with the piperidine or piperazine nitrogen atom; and

B is chosen from:

a) a remainder with the formula:

wherein: R 1 and R 2 are independently selected from hydrogen, halogen, lower alkyl and trifluoromethyl; and

Y is selected from oxygen, sulfur and substituted nitrogen of the formula J^N-L wherein L is selected from hydrogen, lower-alkyl, lower-alkylcarbonyl, lower-alkyloxycarbonyl-lower-alkyl, carboxy-lower-alkyl, phenyl, phenylmethyl, lower- alkylaminocarbonyl, hydroxymethyl and lower-alkenyl, provided that when Y is 0

£1. 12

or^S.are R _and R!1 .hydroqene,...Ar oq:Ar . both„phenyl.,. A. equal, N and n equal 3; _pg.

b) a residue with the formula:

1 2

wherein: R and R are independently selected from hydrogen, halogen, lower alkyl and trifluoromethyl; and

M is selected from hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, lower alkylthio, amino, lower alkylcarbonylamino, lower alkoxycarbonylamino and cycloalkyl with from 3-6 carbon atoms.

As used above and in the following, the term "lower alkyl" is intended to include straight-chain and branched hydrocarbon residues with from 1-6 carbon atoms such as e.g. methyl,

ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl, hexyl and the like; "lower-alkenyl" is intended to include straight and branched alkenyl radicals with from 2-6 carbon atoms such as e.g. ethenyl, 1-methylethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-pentenyl, 2-hexenyl and the like; "cycloalkyl" denotes cyclic hydrocarbon residues with from 3-6 carbon atoms such as e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the term "cnH2n" denotes straight and branched alkylene chains of from 2-6 carbon atoms with at least 2 carbon atoms in the linear part of the chain connecting the B group to the piperidine or piperazine nitrogen atom, such as e.g. 1,2-ethanediyl, 1,3-propanediyl, 2-methyl-1,3-propanediyl, 1,4-butanediyl, 2-methyl-1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, etc. ; and the term "halogen" refers to halogens of atomic weight less than 127, ie fluorine, chlorine, bromine and iodine.

In the state of the art, a number of 1-[(hetero-cyclyl)alkyl]piperazines and a number of 1-substituted 4-(diarylmethyl)piperazine and 4-(diarylmethoxy)piperidine derivatives with pharmacological properties can be found. Such compounds are described e.g. in US Patent Nos. 3,362,956, 3,472,854, 3,369,022, 2,882,271 and 3,956,328 and "Chemical Abstracts", 64, 3499e (1966).

The compounds according to the invention differ from those,

described in the literature, essentially by the nature of the B-C n H2„ n group in the 1-position in the piperazine or piperidine group, and/or by the nature of the diarylmethyl or diarylmethoxy group in the 4-position in the piperazine, respectively. the piperidine group.

The compounds of formula (I), apart from those where B stands for a 2-amino-1H-benzimidazol-1-yl residue, can conveniently be prepared by reacting a suitable reactive ester with formula (II) where n is as stated above , B as above except for a 2-amino-1H-benzimidazol-1-yl residue of the formula:

1 2

where R and R are as indicated above, and W is a suitable reactive ester function derived from the corresponding alcohol such as e.g. halogen, methanesulfonyl, 4-methylbenzenesulfonyl and the like, with a suitable piperidine or piperazine derivative of the formula (III) where A, m,

1 2

Ar and Ar are as stated above:

The preceding condensation reaction is conveniently carried out in a suitable reaction-inert organic solvent such as e.g. a lower alkanol, e.g. ethanol, methanol, propanol, butanol, etc. alkanols; an aromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene, etc.; an ether, e.g. 1,4-dioxane, 1,1'-oxybispropane and the like; a ketone, e.g. 4-methyl-2-pentanone; N,N-dimethylformamide; nitrobenzene; beer. The addition of a suitable base such as e.g. and alkali metal or alkaline earth metal carbonate or hydrogen carbonate can be used to capture the acid released during the reaction. A small amount of a suitable metal iodide, eg sodium or potassium iodide can be added as a reaction promoter.

Somewhat elevated temperatures are beneficial for increasing the reaction rate and the reaction is preferably carried out at the reflux temperature of the reaction mixture.

In this and the following preparations, the reaction products are separated from the reaction mixture and, if necessary, further purified using generally known methods.

The compounds with the formula (I) where B stands for a 2-amino-1H-benzimidazol-1-yl residue (I-a) are easily prepared starting from the corresponding compounds (i) where B denotes a 2-Clower alkyloxycarbonylamino) -1H-benzimidazol-1-yl residue (1-b) by decarboxylation of the latter under hydrolytic conditions, e.g. by acid hydrolysis using a suitable strong acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or by alkaline hydrolysis using a suitable strong base such as e.g. sodium or potassium hydroxide.

It should be noted that when the B group in the compound of formula (I) or an intermediate thereof, represents 2-QLavere-alkyloxycarbonylamino)-1H-benzimidazol-1-yl- or a 2-(lower-alkylcarbonylamino)-1H-benzimidazole -1-yl residue, said residues can be present in different tautomeric forms as shown below: Such tautomeric forms for the compounds of formula (I) naturally lie within the scope of the invention.

Compounds with the formula (I), which can be represented by the formula (I-c):

12 12

where R , R , n, A, Ar and Ar are as indicated above, can alternatively be prepared by cyclization of a suitable intermediate of the formula IV with a suitable cyclizing agent, as known in the art, for the preparation of 1,3-dihydro-2H -benzimidazol-2-ones from 1,2-benzenediamines.

Suitable cyclization agents, which can be used with advantage, include e.g. urea, carbonyl dichloride and alkali metal isocyanates, and the cyclization reaction can be carried out by known methods. When e.g. urea is used as cyclization agent, the compounds (I-c) are easily obtained by stirring and heating the reactants together in the absence of any solvent.

The aforementioned representations can be shown as follows.

The compounds with the formula (I-c) can further be prepared by starting from the corresponding compounds with the formula (V).

12 12 where R , R , n, A, m, Ar and Ar are as indicated above, and P is a suitable protecting group, removal of said protecting group according to conventional methods. As examples of such protecting groups, mention should be made of lower-alkyloxycarbonyl and, a substituted ethenyl group of the formula: 3 4 3 where R and R can represent different groups, but where R is preferably lower-alkyl and R 4 is preferably hydrogen, lower-alkyl or phenyl.

When the protecting group is lower alkyloxycarbonyl, it can be easily removed by alkaline hydrolysis, and when the protecting group is a substituted ethenyl group, it is conveniently eliminated by subjecting the appropriate intermediate (V) to acid hydrolysis. When carrying out the acid hydrolysis to remove the substituted ethenyl group from (V), a wide number of protonic acids can be used, including mineral acids such as e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and further organic acids such as e.g. acetic acid, propanoic acid, ethanedioic acid, etc. acids. Furthermore, the reaction can be carried out in a reaction-inert organic solvent such as is usually used in this type of hydrolytic reaction, e.g. "lower alkanols such as methanol, ethanol, 2-propanol etc.

In a method similar to that described

for preparing the compounds (I-c) from compounds with the formula (IV), compounds with the formula (1-d) can also be prepared:

12

where R , R , n, A, m, Ar and Ar are as indicated above, and M is selected from hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, amino, lower alkoxycarbonylamino and cycloalkyl, by reaction of (IV) with a suitable cyclization agent according to commonly known methods for the preparation of 1H-benzimidazoles from 1,2-benzenediamines. Depending on the nature of M<1> in the compound (I-d) e.g. the following cyclization agents are used.

When M stands for hydrogen, formic acid or a suitable trialkoxymethane can be used as cyclization agent.

When M stands for lower alkyl, phenyl, phenylmethyl or cycloalkyl, a carboxylic acid with the formula can be used:

where R 5 is lower alkyl, phenyl, phenylmethyl or cycloalkyl, or a functional derivative thereof, such as e.g. an acid halide, an ester, an amine or a nitrile derived from such an acid or an iminoester of the formula: where R"* is as defined above; or an aldehyde of the formula:

or an addition product thereof with an alkali metal hydrogen sulphide. When the cyclizing agent is an aldehyde, a suitable oxidizing agent can be added to the reaction mixture, such as e.g. nitrobenzene, mercuric oxide, Cu(II) and Pb(II) salts or other suitable oxidizing agents, as known in the state of the art, or further can. the aldehyde itself serve as an oxidizing agent when added in excess.

When M"<*>" stands for mercapto, it can be used as a cyclizing agent, e.g. carbon disulphide, thiourea, carbon thiodichloride, ammonium thiocyanate etc. are used.

When M"<*>" is an amino group, the ring closure can be carried out with cyanamide or a metal salt thereof, preferably an alkali or alkaline earth metal salt, or with BrCN.

When M"*" stands for lower alkoxycarbonylamino, one can, as a cyclizing agent, e.g. using a suitable lower-alkyl(iminomethoxymethyl)carbamate of the formula (IX): a lower-alkyl[(lower-alkoxycarbonylamino)(R^-thio)methylene]-carbamate of the formula (X):

where R is hydrogen or methyl; or

a lower alkyl carbonyl isothiocyanatidate of formula (XI):

or a lower-alkyl-lower-alkylcarbamothioate of the formula (XII): a di-lower-alkylcyanimidodicarbonate of the formula (XIII) :

The preceding cyclization reactions can all be carried out by following known techniques as described in the literature.

Compounds with the formula (I-e):

can alternatively be prepared by acylation of a suitable 2-amino-1H-benzimidazol-1-yl derivative of the formula (I-a) by following usual N-acylation procedures, e.g. by reacting (I-a) with a suitable lower alkylcarbonyl halide, or with an anhydride derived from a lower alkylcarboxylic acid.

Compounds with the formula (I-f):

12 12 1

where R , R , n, A, m; Ar and Ar are as defined above and L is selected from lower-alkyl, lower-alkylcarbonyl, lower-alkoxycarbonyl-lower-alkyl, carboxy-lower-alkyl, phenylmethyl, lower-

alkylaminocarbonyl, hydroxymethyl and lower-alkenyl, provided that the unsaturation in said lower-alkenyl is in a sty-

ling different from the a-position, can further be produced by introducing said L^" in a compound with the formula (I-c):

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

When L"^ stands for lower-alkyl, lower-alkyloxycarbonyl-lower-alkyl, phenylmethyl or lower-alkenyl, in which case the symbol L"*" a is used, the introduction of said L"*" atyl (I-c) can be carried out by reaction of (I-c) with a suitable reactive ester of the formula L"*" a -W, (XIV), where L is as indicated above, and W has the same meaning as given in the definition of the starting compound with the formula II.

The condensation of (XIV) with (I-c) can be carried out under similar conditions as described above for the condensation of the reactive esters (II) and intermediate products with the formula

(III).

In order to increase the reaction rate, it may be appropriate in some cases to add to the reaction mixture a small amount of a suitable macrocyclic polyether such as e.g. 2,3,11,12-dibenzo-1,4,7,10,13,16-hexaoxacyclooctadeca-2,11-diene as reaction promoter.

When the L "'" group to be introduced is lower alkoxycarbonylethyl, the introduction of the group can alternatively take place by reaction of (I-c) with a lower alkyl-2-propenoate of the formula

(XV) :

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

Compounds with the formula (1-f) where L<1> stands for carboxy-lower alkyl can be easily derived from corresponding lower alkyloxycarbonyl-lower alkyl-substituted compounds by hydrolyzing the latter in the usual way, e.g. with aqueous alkali, to liberate the acid from the ester.

When the L^" group is lower-alkylcarbonyl, the group can conveniently be introduced by reaction between (I-c) with a suitable acylating agent derived from the corresponding lower-alkylcarboxylic acid, such as, for example, a halide, preferably the chloride, or an anhydride, followed by by standard N-acylation procedures.

When L"<*>" stands for lower-alkylaminocarbonyl, it can be introduced by reacting (I-c) with a suitable isocyanatoalkane in a suitable reaction-initiated organic solvent such as e.g. an ether, e.g. 1,1'-oxybisethane, 2,2<1->oxybispropane, 1,4-dioxane, etc.

When L"*" is a hydroxymethyl group, it is conveniently introduced by reacting (I-c) with formaldehyde in a suitable organic solvent such as e.g. N,N-Dimethylformamide.

Compounds with the formula (I-g):

1 2 where B, n, Ar and Ar are as stated above, can alternatively be prepared by condensation of a piperazine derivative of the formula (XVI) with a suitable reactive ester of the formula (XVII) in which Ar"*", Ar 2 and W are as indicated above, under conditions corresponding to those described above for the preparation of the compounds (I) from (II) and (III).

A number of intermediates F with the formula (II) are known compounds and some of them are described in US-PS 4,066,772 and NO-PS 144,296. and they can all be produced by following per se known methods"; Depending on the nature of B in said intermediates "(TI)" the following "procedures can be used for their production.

Intermediates of the formula (II-a)

can be produced as follows:

A suitable substituted 2-chloronitrobenzene with the formula (XVIII) is reacted with a suitable aminoalkanol (XIX) by boiling the reactants together under reflux in a suitable reaction-initiated organic solvent such as, for example a lower alkanol,

e.g. ethanol, propanol, 2-propanol, butanol etc., whereby a [(2-nitrophenyl)amino]alkanol with the formula (XX) is formed, which is then subjected to a reduction from nitro to amine, e.g. by catalytic hydrogenation using a Raney nickel catalyst. The intermediate product (XXI) thus obtained is then reacted with a suitable cyclizing agent as described above, to produce

ling of the compounds (I-c) from (IV), and the thus obtained alcohol with the formula (XXII) is then converted into the desired reactive ester (II-a) using methods known per se. The halides are conveniently prepared by reacting (XXII) with a suitable halogenating agent such as e.g. sulfinyl chloride, sulphuryl chloride, phosphoryl chloride, phosphorous pentabromide, phosphoryl chloride, etc. When the reactive ester is an iodide, it is preferably derived from the corresponding chloride or bromide by replacing halogen with iodine. Other reactive esters, such as methanol sulfonates and 4-methylbenzene sulfonates, are obtained by reacting the alcohol with a suitable sulfonyl halide such as e.g. methanesulfonyl chloride and 4-methylbenzenesulfonyl chloride.

The preceding reactions are illustrated more clearly in the following diagram.

Alternatively, the intermediates of the formula (II-a) can also be prepared by: 1) reacting a compound of the formula (XXIII) in which R 3 and R 4 are as indicated above with a haloalkanol of the formula (XXIV) by appropriate N-alkylation methods in order to obtaining an alcohol of the formula (XXV);

2) conversion of the hydroxyl function in OCXV) to a reactive one

ester group in the usual manner as described previously; and

3) elimination of the substituted ethenyl group in the thus obtained (XXVI) by acid hydrolysis as described above for the preparation of (I-c) from (V).

The introduction of the hydroxyalkyl chain into (XXIII) to obtain (XXIV) can also be carried out by reacting (XXIII) with a suitable 2-(haloalkyloxy)tetrahydro-2H-pyran of the formula (XXVII), which gives an intermediate of the formula (XXVIII ),

where the ether function is hydrolytically split, e.g. by treatment with an aqueous hydrochloric acid solution.

When the reactive ester (II-a) is a halide (II-a-1), this can conveniently be prepared by reaction of (XXIII) with an equivalent amount of a suitable dihaloalkane (XXIX) in the presence of a suitable strong base such as e.g. sodium methoxide, or by following a Mackosza procedure using aqueous alkali and a quaternary ammonium catalyst, e.g. N,N,N-triethylbenzene-methanaminium chloride, giving an intermediate of the formula (XXVI-a), where the substituted ethenyl group is then removed by acid hydrolysis, to obtain the desired halide (II-a-1).

It should be noted that the same procedure also

can be used when the substituted ethenyl group is replaced by another suitable protecting group, except that its removal must follow usual methods for eliminating the special group in question.

The preceding reactions are better illustrated by the following diagrams.

The intermediates of the formula (II-b):

1 2 2 wherein—R-, R , n and W are as indicated above and L is selected from lower-alkyl, lower-alkenyl, lower-alkyloxycarbonyl-lower-alkyl, phenyl, phenylmethyl and lower-alkylaminocarbonyl, can conveniently be prepared by introduction of the reactive ester side chain in a starting material with the formula (XXX):

by following conventional procedures as described above for the preparation of the intermediates (XXVI) from (XXIII).

Intermediates of the formula (II-c):

can be prepared by starting from the corresponding (II-a) by hydroxymethylation of the latter in the usual way with formaldehyde.

Intermediates of the formula (II-d): except those in which M denotes a mercapto group or a lower alkylthio group, are conveniently obtained by introducing the reactive ester side chain into a starting material of the formula (XXXI):

The introduction of the CnH2n-W group can be carried out by following procedures corresponding to those described above for the introduction of said group into the starting materials with the formula (XXIII).

Intermediates of the formula (II-e):

12 1 in which R , R , M , n and W are as indicated above, can be prepared by subjecting a suitable alcohol of formula (XXI) to cyclization with a suitable cyclizing agent as described above, followed by conversion of the hydroxyl group in the thus obtained intermediate with the formula (XXXII) to a reactive ester group.

The intermediates of the formula (II-f):

is conveniently achieved by S-alkylation of a suitable intermediate of the formula (XXXII) wherein M<1> denotes mercapto (XXXII-a), by following standard S-alkylation procedures, e.g. with a suitable halogen-lower-alkane and subsequent conversion of the hydroxyl function in the thus obtained compound (XXXIII) into a reactive ester group:

Intermediates of the formula (II-g):

NH -CO-(lower alkyl)

in

N N-C H„ -W

is suitably prepared by N-acylation of the corresponding amino-substituted analogue (II-h):

by following methods known to the person skilled in the art, e.g. by reacting (II-h) with a suitable lower alkyl carbonyl halide or with an anhydride derived from a suitable lower alkyl carboxylic acid.

The intermediates of the formula (IV) are obtained by condensation of a suitable reactive ester of the formula (XXXIV) with a piperazine or piperidine derivative of the formula (III) followed by reduction of the nitro group in the thus obtained intermediate (XXXV) to an amino group according to standard reaction procedures ways of reduction of nitro to amine, e.g. by reacting the nitro compound with nascent hydrogen or by catalytic hydrogenation in the presence of suitable catalysts such as e.g. Raney nickel:

The reactive esters with the formula (XXXIV) which are used as starting materials are easily prepared from an alcohol with the formula (XX) by converting the hydroxyl function in this to a reactive ester group by following standard procedures as described above. The intermediates of formula (V) can be obtained by condensation of a reactive ester of formula (XXXVI) with a piperazine or piperidine derivative of formula (III):

The reactive ester (XXXVI), which is used as starting material, is prepared by introducing the CnH2nW group into a starting material with the formula (XXXVII):

by following procedures as described above. The intermediates of the formula (XVI) can be prepared by the reaction of a reactive ester of the formula (II) with a piperazine derivative of the formula (XXXVIII) in which Q is a suitable protecting group such as e.g. phenylmethyl or lower alkyloxycarbonyl, and subsequent elimination of the protecting group Q from the thus obtained intermediate (XXXIX) by following standard methods known in the art, e.g. by catalytic hydrogenation using palladium-on-charcoal when Q is phenylmethyl, or by alkaline hydrolysis when Q is lower alkyloxycarbonyl:

Intermediates of the formula (XVI-a): can alternatively be prepared by reacting (XXXVI) with (XXXVIII) to obtain an intermediate of the formula (XL) and subsequent elimination of the protecting groups P and Q by suitable methods as known in the art .

The intermediates of the formula (III) where A is J!>N- and

m is 0, (III-a), are generally known and they can all be prepared using known methods. Such intermediate products (III-a) can e.g. is prepared by first subjecting a suitable aroyl halide to a Friedel-Crafts reaction with a suitable arene to obtain an Ar , Ar <2->methanone which is then reduced in the usual way, e.g. with sodium borohydride, to the corresponding methanol. This latter is then converted to a reactive ester (XVII) in the usual manner for the preparation of reactive esters from alcohols,

and the desired intermediates (III-a) are then obtained by reaction between (XVII) and piperazine.

The intermediates of the formula (III) where A is J^CH- and

m is 1, (III-b), can conveniently be prepared by O-alkylation

of a 4-piperidinol of the formula (XLI) in which Q is a suitable protecting group as indicated previously with a suitable reactive ester of the formula (XVII), followed by removal of the protecting group in the thus obtained (XLII) in the usual manner:

The primary starting materials, which are used in all the preceding preparations, are generally known and they can all be prepared by following methods known to the person skilled in the art.

The compounds of formula (I) can be converted into therapeutically active non-toxic acid addition salts by treatment with a suitable acid such as e.g. an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc., or an organic acid such as e.g. Acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanone, 2-oxopropanonic acid, propandionic acid, butanedioic acid, (Z)-2-butenedioic acid, (E)-2-butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, benzoic acid, 3-phenyl-2-propenonic acid, α-hydroxybenzeneacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino- 2-hydroxybenzoic acid etc. Conversely, the salt form can be converted by treatment with alkali into the free base form.

The compounds of the formula (I) and the pharmaceutically acceptable acid addition salts thereof have strong anti-anaphylactic and antihistamine action and as such are useful agents in human and animal therapy. The anti-anaphylactic and anti-histamine properties of the compounds according to the invention are clearly shown by results obtained in the experimental procedures indicated below.

It should be emphasized that the compounds indicated in

the accompanying tables, are not limiting of the invention,

but only to exemplify the useful properties of all compounds within the scope of formula (I).

A. Materials and methods

a) Antianaphylactic effect and antihistaminic effect in vivo

The antianaphylactic and antihistamine effects of

the present compounds (I) and their salts have been studied in vivo in guinea pigs.

Guinea pigs weighing between 400 and 500 g are sensitized to ovalbumin by subplantar injection of 0.05 ml antiserum into a left hind paw. The animals are then starved and treated 24 hours after the sensitization orally with saline solution (control animals) or a special dose of the compound under investigation.

The histamine injection in a dose of 50 µg was given subplantarly in the right hind paw 2 hours after the oral pretreatment with the compound. The diameter of both hind paws is measured only after the administration of the histamine injection and 10 min. thereafter. The animals are then given intravenously 0.6 mg ovalbumin for 30 min. after the histamine injection. All control animals developed typical primary anaphylactic shock symptoms (cough, breathing difficulties, convulsions) and 85% of these control animals died within 15 min. after the ovalbumin injection. Protection against death is used as a criterion for any drug effect, and the calculated ED,-q value, i.e. the oral dose at which protection is noted in 50%

of the animals, are indicated in the following tables.

The mean histamine graft edema in 200 control animals 10 min. after the histamine injection is 15 units (1 unit = 0.1 mm). Reactions below 10 units, which occurred in less than 5%

of the control animals, is defined as effective inhibition of histamine edema in the compound-treated animals, and the levels for the oral dose at which this effective inhibition is seen are also indicated in the tables.

b) Antihistamine activity in vitro

Ileum strips from guinea pigs are suspended in a 100 ml

Tyrode bath at 37.5°C with a preload of 0.75 g and gas-treated with 95% O 2 and 5% CC 2 .

Histamine (0.5 mg/l) induced spasms are noted kymographically with an isotonic arm that provides a five-fold magnification. The mutual influence between the compound to be tested (5 min. incubation time) and the agonist is studied and the tables below give the effective concentration in mg/l for the various compounds whereby a significant inhibition (50%) of the histamine-induced contraction is measured.

As a result of the above aiigjLtt_e_p_røver, the subject compounds (I) and the pharmaceutically acceptable salts thereof have generally been found effective as antiallergic agents, in dosages from about 0.25 to about 20 mg/kg body weight when systematically administered to warm-blooded animals .

In view of the useful antihistamine action and anti-anaphylactic action, the compounds according to the invention can be formulated into different pharmaceutical forms for administration purposes. For the preparation of the pharmaceutical preparations, an effective amount of the compound in base or acid addition salt form is combined as active ingredient, but a thorough mixture with a pharmaceutically acceptable carrier, which carrier may have any suitable form.

These pharmaceutical preparations are desirable in form

of unit doses, preferably for oral, rectal or parenteral administration. For oral administration in dosage form, water, glycols, oils, alcohols etc. can be used for the production of suspensions, syrups, elixirs and solutions, or solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrating agents etc. when powders, pills, capsules and tablets are produced. Because of the ease of administration, tablets and capsules represent the most advantageous forms of oral dosage units.

For parenteral compositions, the carrier will usually comprise sterile water, at least principally, although other ingredients may be incorporated to aid solubility. Injectable solutions can e.g. is prepared where the carrier comprises a salt solution, a glucose solution or a mixture of salt and glucose. Injectable suspensions can also be prepared where suitable liquid carriers, suspending agents etc. used. Acid addition salts of I are obviously more suitable for the preparation of aqueous preparations due to their increased water solubility compared to the corresponding base form.

It is particularly advantageous to formulate the above

said pharmaceutical preparations in dosage units to facilitate administration and dosage uniformity. Dosage units as used denote physically discrete units suitable as unit doses, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in conjunction with the required pharmaceutical carrier. Examples of such unit doses are tablets of all types, capsules, pills, powder packets, injectable solutions or suspensions, etc.

The following examples shall illustrate the invention in more detail - All parts are given on a weight basis, unless otherwise stated.

Preparation of starting materials:

Example I

To a stirred and warm mixture of 54 parts of 1,3-dihydro-1-(phenylmethyl)-2H-benzimidazol-2-one, 47.25 parts of 1-bromo-3-chloro-propane and 6 parts of N,N ,N-triethylbenzenemethanaminium chloride is added dropwise to 450 parts of sodium hydroxide solution (60%) at 60°C. After the addition is complete, stirring is continued for 6 hours at 60°C. The reaction mixture is cooled and poured onto water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated, and the residue is crystallized from 2,2<1->oxybispropane, whereby after drying 42 parts (58%) of 1-(3-chloro-propyl)-1,3-dihydro-3-( phenylmethyl)-2H-benzimidazol-2-one.

In the same way, it was produced:

Example II

By following the procedure in ex. In and by using an equivalent amount of a suitable 1H-benzimidazole as starting material, the residue was obtained:

Example III

A mixture of 20 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol, 50 parts of acetic acid and 150 parts of 4N hydrochloric acid solution is stirred and boiled under reflux overnight. 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. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2<1->oxybispropane and 6.5 parts or 28% of 5-chloro-2-methyl-1H-benzimidazol-1-propanol are obtained.

In the same way, 5-chloro-2-ethyl-1H-benzimidazole-1-propanol was prepared by reacting 3-[(2-amino-4-chloro-renyl)amino]-1-propanol with propanoic acid.

. Example IV

To a stirred and under reflux (water separator)

• heated mixture of 30 parts of 3-[(2-amino-4-chlorophenyl)aminoj-l-propanol and 0.1 parts of 4-methylbenzenesulfonic acid j 405 parts of methyl]-

benzene is added dropwise to a solution of 34 parts cyclohexane-carboxaldehyde in 45 parts methylbenzene. When addition is complete, stirring is continued for 1 hour at reflux temperature and with a water separator. Methylbenzene is removed by evaporation in vacuo and the residue is triturated in 2,2<1->oxybispropane. The product is filtered off and dried and 16.5 parts or 38% of 5-chloro-2-cycl6hexyl-1H-benzimidazole-1-propanol with a melting point of 95°C is obtained.

Example V

A mixture of 30 parts of 3-[(2-amino-4-chlorophenyl)amino]"-1-propanol, 44.8 parts of sodium α-hydroxybenzeneethanesulfonate and 120 parts of ethanol is stirred and refluxed for 30 min. The reaction mixture is evaporated and the residue is taken up in water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated, and 45 parts or 100% of 5-chloro-2-(phenylmethyl)-1H-benzimidazole-1-propane are obtained as a residue.

In the same way, 6-chloro-2-cyclohexyl-1H-benzimidazole-1-propanol with a melting point of 120.1°C was prepared by reacting 3-[(2-amino-5-chlorophenyl)amino]-1-propanol with sodium α-hydroxycyclohexanemethanesulfonate.

Example VI

To a stirred mixture of 93 parts of 3-(2-aminophenyl)-amino-l-propanol, 45.5 parts of potassium hydroxide and 600 parts of 85% ethanol in water, 60.8 parts of carbon disulphide are added dropwise.

After complete dissolution, stirring is continued for 6 hours at room temperature. The reaction mixture is evaporated and the residue taken up in 1500 parts of water. The whole is filtered over hyflo and the filtrate is acidified with acetic acid. The oily product solidifies when scraped. It is filtered off, washed with water and dried, and 92 parts or 78.9% of 2-mercapto-1H-benzimidazole-1-propanol with melting point 110°C is obtained.

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 over hyflo and the filtrate made alkaline with solid potassium hydroxide. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated, and 19 parts or 85.5% of 2-(methylthio)-1H-benzimidazole-1-propanol are obtained as a residue.

11.5 parts of methanesulfonyl chloride are added dropwise to a stirred mixture of 19 parts of 2-(methylthio)-1H-benzimidazol-1-propanol, 15.2 parts of N,N-diethylethanamine and 195 parts of dichlorometal. After the addition is complete, stirring is continued for 1 hour at reflux temperature. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated, and 19 parts of 3-[2-(methylthio)-1H-benzimidazol-1-yl]propylmethanesulfonate are obtained as an oily residue.

Example 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 stirred and heated under reflux overnight. The reaction mixture is cooled to room temperature, filtered, and the filtrate is evaporated. The residue is stirred in water and acidified with a dilute hydrochloric acid solution. The whole thing is stirred and heated for 30 min. in a water bath. After cooling to room temperature, the product is extracted with methylbenzene. The aqueous phase is separated and made alkaline with ammonium hydroxide. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated, and 50 parts of 1H-benzimidazole-1-butanol are obtained as an oily residue.

Example VIII

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

In the same way, the following 1-(chloroalkyl)-1H-benzimidazoles are prepared:

Example 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 stirred under reflux temperature. overnight. Butanol is removed by evaporation in a vacuum, and water is added to the residue. The product is extracted with 4-methyl-2-pentanone. The extract is washed several times with water, dried, filtered and evaporated. The oily residue is purified by column chromatography over silica gel using a mixture of trichloromethane and 5% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of 2,2'-oxybispropane and 2-propanol, and 31.7 parts of 3-[(4,5-dichloro-2-nitrophenyl)-amino]-1-propanol with melting point 97°C.

In the same way: 3-{[2-nitro-4-(trifluoromethyl)phenyl]amino}-1-propanol; and 2-{[2-nitro-4-(trifluoromethyl\phenyl]amino}ethanol; with melting point 74.9° C. Example X

To a stirred mixture of 39.2 parts of 3-(2-nitrophenyl)-amino-1-propanol and 225 parts of trichloromethane, 35.7 parts of sulfinyl chloride are added dropwise (exothermic reaction; the temperature rises to 45°C). After the addition is complete, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated, and 43 parts or 100% of N-(3-chloropropyl)-2-nitrobenzene-amine is obtained as a residue.

Similarly, there was prepared: N-(3-chloropropyl)-2-nitro-4-(trifluoromethyl)benzenamine as a residue; 4,5-dichloro-N-(3-chloropropyl)-2-nitrobenzenamine, melting at 78°C; and

N-(2-chloroethyl)-2-nitro-4-(trifluoromethyl)benzenamine.

Example XI

A mixture of 21.5 parts of N-(3-chloropropyl)-2-nitrobenzenamine, 22.68 parts of 1-(diphenylmethyl)-piperazine, 20 parts of N,N-diethylethanamine and 180 parts of N,N-dimethylacetamide is stirred and heated for 6 hours at 100°C. The reaction mixture is evaporated, and the residue is taken up in water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated.

The residue is crystallized from a mixture of 2-propanol, ethanol and 2,2'-oxybispropane. The product is filtered off and dried, and 15.5 parts or 36.9% of 4-(diphenylmethyl)-N-(2-nitrophenyl)-1-piperazinepropamine hydrochloride with melting point 2 28°C are obtained.

Similarly, there was prepared: N-(4,5-dichloro-2-nitrophenyl)-4-(diphenylmethyl)-1-piperazinepropamine as a residue;

4-(diphenylmethyl)-N-[2-nitro-4-(trifluoromethyl)-phenyl]-1-piperazine-propanamine of melting point 113.7°C; and

4-(Diphenylmethyl)-N-[2-nitro-4-(trifluoromethyl)-phenyl]-1-piperazine-ethanamine with a melting point of 152.1°C.

Example XII

A mixture of 15 parts of 4-(diphenylmethyl)-N-(2-nitro-phenyl)-1-piperazinepropamine hydrochloride in 160 parts of methanol is hydrogenated at ordinary pressure and at room temperature with 5 parts of Raney nickel. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off over 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, and 12 parts or 78.9% of N-(2-aminophenyl)-4-(diphenylmethyl)-1-piperazinepropanamine hydrochloride with melting point 223.1°C are obtained.

In the same manner was prepared: 4,5-dichloro-N<1->{3-[4-(diphenylmethyl)-1-piperazinyl]-propyl}-1,2-benzenediamine as an oily residue; N<1->{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-4-(trifluoromethyl)-1,2-benzenediamine and

N<1->{2-[4-(diphenylmethyl)-1-piperazinyl]ethyl}-4-(trifluoromethyl)-1,2-benzenediamine as an oily residue.

Example XIII

A mixture of 60.5 parts 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylphenyl)-2H-benzimidazol-2-one, 31.68 parts 1-(phenylmethyl)-piperazine, 21 .2 parts of sodium carbonate, 0.1 parts of potassium iodide and 400 parts of 4-methyl-2-pentanone are stirred and heated under reflux for 20 hours 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, and 70 parts or 100% of 1,3-dihydro-1-(1-methylethenyl)-3~{3-[4-(phenylmethyl)-1-piperazinyl]propyl }- are obtained 2H-benzimidazol-2-one as a residue.

On the same was prepared: 1,3-dihydro-1-{2-[4-(phenylmethyl)-1-piperazinyl]ethyl}-2H-benzimidazol-2-one with melting point 136.5°C.

Example XIV

To a stirred solution of 70 parts of 1,3-dihydro-1-(1-methylethenyl)-3-{3-[4-(phenylmethyl)-1-piperazinyl]-propy]}-2H-benzimidazol-2-one in 240 parts of ethanol are added to 55 parts of 6N hydrochloric acid solution. The whole thing is stirred for 2 hours at 40-50°C. The reaction mixture is evaporated, and the residue is taken up in a dilute ammonium hydroxide solution. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 63 parts or 100% of 1,3-dihydro-1-{3-[4-(phenylmethyl)-1-piperazinyl]propyl}-2H-benzimidazol-2-one as a residue .

Example XV

A mixture of 63 parts of 1,3-dihydro-1-{3-[4-(phenylmethyl)-1-piperazinyl}propyl]-2H-benzimidazol-2-one in 400 parts of methanol is hydrogenated at ordinary pressure and at room temperature with 10 parts. 10% palladium on charcoal. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off over 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 and 29.5 parts or 63% of 1,3-dihydro-1-[3-(1-piperazinyl)propyl]-2H-benzimidazol-2-one with melting point 157.5°C is obtained. The following was prepared in the same way: 1,3-dihydro-1-[2-(1-piperazinyl)ethyl]-2H-benzimidazol-2-one with melting point 122.6°C.

Example XVI

To a stirred mixture of 20 parts of aluminum chloride and 100 parts of fluorobenzene, 20.5 parts of 2,4-dichlorobezoyl chloride are added dropwise. After complete addition, the mixture is heated to reflux temperature and stirred at this temperature for 5 min. The reaction mixture is poured onto crushed ice, and the product is extracted with 1,1<1->oxybisethane. The extract is dried and evaporated, and 30 parts of (2,4-dichlorophenyl)(4-fluorophenyl)methanone are obtained as an oily residue.

In the same way: (4-fluorophenyl)(4-pyridinyl)methanone with a melting point of 85.5°C is prepared.

Example XVII

To a stirred and heated to reflux temperature mixture of 23.4 parts of (4-chlorophenyl)(2-fluorophenyl)methanone in 280 parts of 2-propanol, 3.7 parts of sodium borohydride are added in portions. After the addition is complete, stirring is continued for 2 hours at the reflux temperature, + 80°C. The reaction mixture is cooled and decomposed by the addition of water. The 2-propanol is evaporated, and the remaining product is extracted with trichloromethane. The extract is dried, filtered and evaporated, and 23.6 parts of 4-chloro-α-(2-fluorophenyl)benzenemethanol are obtained as a residue.

In the same way: 2,4-dichloro-α-(4-fluorophenyl)benzenemethanol is prepared as a residue; α-(4-fluorophenyl)-4-pyridinemethanol, melting point 138.2°C; α-(4-Fluorophenyl)-3-pyridinemethanol hydrochloride, m.p. 158.3°C; and

4-Methoxy-α-[3-(trifluoromethyl)phenyl]benzenemethanol as a residue.

Example XVIII

A mixture of 22 parts of 2,4-dichloro-α-(4-fluorophenyl)-benzenemethanol and 240 parts of 12N hydrochloric acid solution is stirred for 40 hours at room temperature. The reaction mixture is poured onto ice water and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is distilled and 13.2 parts of 2,4-dichloro-1-[chloro-(4-fluorophenyl)methyl]-benzene with boiling point 14 6°C at 0.15 mm pressure are obtained.

In the same way: 1-[α-chloro-α-(4-methoxyphenyl)methyl]-3-(trifluoromethyl)benzene is prepared as a residue; and

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

Example XIX

To a stirred mixture of 23.6 parts of 4-chloro-α-(2-fluoro-phenyl)benzenemethanol in 108 parts of benzene is added dropwise 24

parts sulfinyl chloride. After the addition is complete, the whole is heated to reflux temperature and the stirring is continued initially for 5 hours at reflux temperature and further overnight at room temperature. The benzene is evaporated, and the remainder is distilled, and

nlr 16.5 parts 1-chloro-4-[α-chloro-α-(2-fluorophenyl)methyl]benzene,

with boiling point 122-125°C at 0.1 mm Hg.

In the same way, the following is produced:

3-[α-Chloro-α-(4-fluorophenyl)methyl Jpyridine hydrochloride as an oil

like residue;

3-[α-chloro-α-(4-chlorophenyl)methyl]pyridine hydrochloride as a residue; 4-[α-chloro-α-(4-fluorophenyl)methyl]pyridine hydrochloride with melting point 198-200°C;

1-(Chlorophenylmethyl)-2,3-dimethylbenzene boiling at 137°C at 0.7 mm Hg;

1-(Chlorophenylmethyl)-2,4-dimethylbenzene with a boiling point of 137°C at 0.7

mm Hg;

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

mm Hg; and

1-(Chlorophenylmethyl)-2-fluorobenzene with boiling point 108-109°C at 0.4

mm Hg.

Example XX

A mixture of 121 parts of piperazine, 54 parts of 3-[α-chloro-α-(4-chlorophenyl)methyl]pyridine hydrochloride and 315 parts of N,N-dimethylformamide is stirred for 20 hours at room temperature. reaction mix-

none is evaporated and 250 parts of water are added to the residue. Product

tet is extracted with methylbenzene. The organic phase is washed with water and extracted with a 10% acetic acid solution. The acidic aqueous phase is made alkaline with a 60% sodium hydroxide solution and the product is extracted again with methylbenzene. The extract is dried, filtered and evaporated. The oily residue is converted to the nitrate salt in ethanol. The salt is filtered off, washed with ethanol and with 2,2<1->oxybispropane and crystallized from ethanol, and 48 parts of 1-[α-(4-chlorophenyl)-α-(3-pyridinyl)methyl]piperazine trinitrate are obtained with melting point 13 2.9°C.

The following was prepared in the same way: 1-[α-(4-chlorophenyl)-α-(2-fluorophenyl)methyl]piperazine; 1-[α-(4-Fluorophenyl)-α-(4-pyridinyl)methyl]piperazine with melting point 108.4°C; 1-[(2-chlorophenyl)(3-chlorophenyl)methyl]piperazine;

1-[(2-fluorophenyl)phenylmethyl]piperazine ethanedioate (1:1), with melting point 195.5°C;

1-[(4-fluorophenyl)(4-methoxyphenyl)methyl]piperazine ethanedioate (1:2), with melting point 280.1°C; and

1-[(4-nitrophenyl)phenylmethyl]piperazine dihydrochloride.

Example XXI

A mixture of 21.5 parts of ethyl 4-hydroxy-1-piperidine carboxylate, 32.5 parts of bis(4-fluorophenyl)bromomethane and 8.6 parts of potassium carbonate is stirred and heated in an oil bath at 140° C. for 3 hours. The reaction mixture is allowed to cool to room temperature and water is added. The product is extracted with methylbenzene. The extract is washed successively with water, a dilute hydrochloric acid solution and a sodium bicarbonate solution, dried, filtered and evaporated. The process is distilled off (boiling point 143°C at 0.5-1 ml Hg), and 29 parts of ethyl 4-[bis(4-fluorophenyl)methoxy]-1-piperidinecarboxylate are obtained as an oily residue.

In a similar manner, it was prepared: ethyl 4-(diphenylmethoxy)-1-piperidine carboxylate with a boiling point of 150°C at 0.4 mm Hg.

Example XXII

A mixture of 29 parts of ethyl 4-[bis(4-fluorophenyl)methoxy]-1-piperidine carboxylate, 25 parts of potassium hydroxide, 1 part of water and 160 parts of 2-propanol is stirred and refluxed for 4 hours. The solvent is evaporated, and water is added to the residue. The product is extracted with methylbenzene. The extract is washed several times with water, dried, filtered and evaporated.

The oily residue is converted to the hydrochloride salt in 4-methyl-2-pentanone and 2-propanol at room temperature. The salt is filtered off and dried, and 20.5 parts or 78% of 4-[bis(4-fluorophenyl)-methoxy]piperidine hydrochloride with a melting point of 161.8°C is obtained.

The following was prepared in the same way: 4-[alpha]phenylmethoxy)piperidine hydrochloride with a melting point of 209.8°C.

Manufacture of end products:

Example 1.

A mixture, of 5.3 parts 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5 parts 1-(diphenylmethyl)piperazine, 6.4

parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone are stirred and. is heated to reflux overnight with a water separator. 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 a mixture of trichloromethane and 5% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oil-active residue is crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol. The product is filtered off and dried, and 2 parts or 23% of 1-{3-[4-(diphenylmethyl)-1-piperazinyl] propyl}-1, 3-dihydro-2H-benzimidazol-2-one with a melting point of 153 .6°C.

Similarly, the following compounds were prepared in

free base form and in the form of an acid addition salt after treatment of the free base with a suitable acid:

Example 2

In an analogous way as described in ex. XXIII is prepared: 1-[3-{4-bis(4-fluorophenyl)methyl]-1-piperazinyl}-propyl-1,3-r dihydro-2H-benzimidazol-2-one with melting point 197.3°C by reacting 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate with 1[-bis(4-fluorophenyl)methyl]piperazine;

1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-3-methyl-2H-benzimidazol-2-one dihydrochloride hydrate with melting point 201.8°C by reaction of 1, 3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one with 1-(diphenylmethyl)piperazine;

Example 3

A mixture of 6.95 parts 1-(5-chloropentyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 5.15 parts 1-(diphenylmethyl)piperazine, 5.30 parts sodium carbonate, 0.1 parts potassium iodide and 160 parts 4-methyl-2-peritanone are stirred and heated to reflux overnight with a water separator. The reaction mixture is cooled to room temperature, water is added and the layer is separated. The organic phase is dried, filtered and evaporated. The rest is stirred and boiled under reflux for 30 min. with 12 parts of a hydrochloric acid solution in 40 parts of ethanol. The whole is evaporated, and the residue is crystallized from ethanol, whereby 5 parts or 46% of 1-{5-[4-(diphenylmethyl)-1-piperazinyl]pentyl}-1,3-dihydro-2H-benzimidazol-2-one is obtained -dihydrochloride hydrate with a melting point of 215.3°C.

In the same way, the following is produced:

pp

Example 4

To a stirred solution of 76 parts of 1-{3-[4-(diphenyl-methyl)-1-piperazinyl]propyl}-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one in 280 parts of ethanol are added - 120 parts of salt-acid solution and 250 parts of water. The whole thing is stirred for 30 min. at room temperature. When cooling in an ice bath, fold the product out. This is filtered off, washed with 2-propanone and with 2,2'-oxybispropane and dried, whereby 43 parts or 55% of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3 -dihydro-2H-benzimidazol-2-one dihydrochloride hydrate with melting point 237.5°C.

In a similar way, the following is produced:

Example 5

A mixture of 3.6 parts of N -{2-[4-(diphenylmethyl)-1-piperazinyl]ethyl}-4-(trifluoromethyl)-1,2-benzenediamine and 1.8 parts of urea is stirred for 3 hours in a oil bath at 190°C. The reaction mixture is cooled, water and trichloromethane are added 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. The pure fractions are pooled and the eluent evaporated to yield 1.5 parts or 41.5% of 1-{2-[4-(diphenylmethyl)-1-piperazinyl]-ethyl}-1,3-dihydro-5-( trifluoromethyl )-2H-benzimidazol-2-one with melting point 163.7°C.

In the same way was prepared: 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-5-(trifluoromethyl)-2H-benzimidazol-2-one with melting point 152.7 °C;

and

5,6-dichloro-1-{3-[4-(diphenylmethyl)-1-piperazinyl]-propyl}-1,3-dihydro-2H-benzimidazol-2-one with melting point 214.7°C.

Example 6

A mixture of 2.3 parts of 1-{3-[4-(diphenylmethyl)-1-pipe-erazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one, 4.5 parts of 40%-ig formaldehyde solution and 45 parts of N,N-dimethylformamide are stirred and heated for 2 hours at 100°C. reaction mix-

none is cooled and diluted with water. The precipitated product is filtered off and crystallized from methylbenzene, and after drying 1.5 parts or 66% of 1-{3-[4-(diphenylmethyl)-1-piperazinyl] propyl}-1,3-dihydro-3 -(hydroxymethyl)-2H-benzimidazol-2-one with melting point 102.5°C.

Example 7

A mixture of 1.55 parts of acetic anhydride, 3 parts of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3pdihydro-2H-benzimidazol-2-one and 22.5 parts of methylbenzene is stirred and heated to return overnight. 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. Pure fractions are collected and the eluent: • is evaporated, and 1.1 parts or 33.5% of 1-acetyl-3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3- dihydro-2H-benz-inidazol-2-one with melting point 124.4°C.

Example 8

A mixture of 1.1 parts of ethyl 2-propenoate, 3 parts of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl_}^li3-dihydro-2H-benzimidazol-2-one, a few drops of 40 % N,N,N-trimethylbenzenemethane-amine hydroxide solution in methanol and 25 parts of 1,4-dioxane are stirred and heated to reflux for 24 hours. The reaction mixture is evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5) as eluent. The pure fractions are collected, and the eluent is evaporated. The residue is converted to the hydrochloride salt in 2-propanol and ethanol. The salt is filtered off and dried, and 1.4 parts or 32.5% of ethyl 3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-2,3-dihydro-2-oxo-1H are obtained -benzimidazole-1-propanoate dihydrochloride, dihydrate with a melting point of 204°C.

Example 9

A mixture of 3 parts 1-{3-[4-(diphenylmethyl)-1-piper-azinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one, 1 part isocyanatemethane and 25 parts 1, 4-dioxane is stirred and heated to reflux overnight. The reaction mixture is evaporated, and the residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5) as eluent.

The pure fractions are collected, and the eluent is evaporated. The residue is crystallized from a mixture of methylbenzene and 2,2<1->oxybispropane, and 0.8 parts or 23.5% of 3-{3-[4-(diphenyl-methyl)-1-piperazinyl]propyl}- is obtained 2,3-dihydro-N-methyl-2-oxo-1H-benzimidazole-1-carboxamide with melting point 153.1°C.

Example 1Q

To a stirred mixture of 9.4 parts of 1-{3-[4-(diphenyl-methyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one and 180 parts of methylbenzene is added 0, 8 parts of 75% sodium hydride dispersion, and the whole is stirred and heated for 60 min.

to 90°C. After cooling to 30°C, 0.2 parts of 2,3,11,12-dibenzo-1,4,7,10,13,16-hexaoxacyclooctadeca-2,11-diene are added, and stirring is continued for 10 minutes. 2.4 parts of ethyl 2-bromoacetate are then added, and the mixture is stirred and boiled under reflux overnight. The reaction mixture is cooled to 90°C, after which 50 parts of water are added, and the layers are separated while the whole is hot. The organic phase is evaporated, and 10 parts of ethyl 3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-2,3-dihydro-2-oxo-1H-benzimidazole-1-acetate are obtained as a rest.

A mixture of 9.8 parts ethyl 3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-2,3-dihydro-2-oxo-1H-benzimidazole-1-acetate, 1.2 parts sodium hydroxide and 150 parts water are stirred and boiled under reflux for 5 min. (+ 80°C). The reaction mixture is filtered, and the filtrate is acidified with acetic acid to pH

5,8-6 whereby a sticky precipitate is formed. This separate

res and crystallized from ethanol and water. The product is filtered off and dried in a vacuum at 100°C for 3 hours, and 6 parts of 3-{3-[4-(diphenylmethyl)-1-piperazinylpropyl}-2,3-dihydro-2-oxo-1H- benzimidazole-1-acetic acid hemihydrate with melting point 138.7°C.

Example 1 1

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 N,N-dimethylformamide are stirred and heated overnight to 50°C. The reaction mixture is cooled and poured onto 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<1->oxybispropane. The product is filtered off and dried, yielding 2 parts or 23.4% of 1,3-dihydro-1-3-{4-[phenyl(2-pyridinyl)methyl]-1-piperazinyl}propyl-2H-benzimidazol-2 -on with a melting point of 141.7°C.

In the same way, the following is produced:

Example 12

A mixture of 4.9 parts 1-(3-chloropropyl)-1H-benzimidazole, 5.76 parts 1-[bis(4-fluorophenyl)methyl]piperazine, 5.3 parts sodium carbonate, 0.1 part potassium iodide and 200 parts 4-methyl-2-pentanone is stirred and refluxed for 20 hours 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-petanone and 2,2'-oxybispropane. The product is filtered off and dried, and 5.5 parts or 59.3% of 1-3-{4-[bis( 4-Fluorophenyl)-methyl]-1-piperazinyl}propyl -H-benzimidazole hydrate with melting point 108.4°C.

In the same way, the following is produced:

Example 13

By following the procedure in ex. XXXIV 1-{3-[4-(diphenylmethyl)-1-piperazinyl]-propyl}-2-(methylthio)-1H-benzimidazole trihydrochloride.hydrate with melting point 203.4°C is prepared by reaction of 3-[2-(methylthio) )-1H-benzimidazol-1-yl]propylmethanesulfonate with 1-(diphenylmethyl)piperazine.

Example 14

A mixture of 4.37 parts of N-(2-aminophenyl)-4-(diphenylmethyl)-1-piperazinepropamine hydrochloride, 38 parts of carbon disulfide, 2 parts of sodium carbonate and 40 parts of ethanol is stirred and refluxed for 20 hours. 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. The residue is crystallized from 4-methyl-2-pentanone, and 2 parts or 45.5% of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazole- 2-thion with melting point 181.8°C.

Example 15

A mixture of .60 parts of N-(2-aminophenyl)-4-(diphenyl-methyl)-1-piperazinepropanamine, 20 parts of methyl(iminomoethoxymethyl) carbamate, 42 parts of acetic acid and 450 parts of trichloromethane is stirred and refluxed overnight. The reaction mixture is evaporated, and the residue is stirred in water. The latter is decanted off, and the remainder is taken up again in water. The whole is made alkaline with a dilute ammonium hydroxide solution, and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:50) as eluent.

The pure fractions are collected, and the eluent is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, and 13.5 parts of methyl-1-{3-[4-(diphenyl-methyl)-1-piperazinyl]propyl} are obtained -1H-benzimidazol-2-yl carbamate with melting point 137.8°C.

A mixture of 12 parts methyl-1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1H-benzimidazol-2-yl carbamate, 60 parts concentrated hydrochloric acid solution and 80 parts methanol is stirred and refluxed overnight . The reaction mixture is evaporated, and water is added to the residue. The free base is liberated in the usual way 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, and 4.3 parts or 40% of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]-propyl}-1H-benzimidazol-2-amine with melting point 228.7°C is obtained .

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 is stirred and refluxed for 5 hours. The reaction mixture is evaporated, and the residue is stirred in water. The whole is made alkaline with ammonium hydroxide, and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from ethanol. The product is filtered off and dried, and 6.6 parts or 56.5% of N-1-{3-[4-(diphenylmethyl)]-1-piperazinyl propyl}1,3-dihydro-2H-benzimidazol-2- ylidene acetamide with melting point 143.3°C.

Example 1 6

A mixture of 13 parts of 1,3-dihydro-1-[3-(1-piperazinyl)propyl]-2H-benzimidazol-2-one, 12.4 parts of 1,1'-(bromomethylene)-bis[benzene ], 6.6 parts sodium carbonate and 200 parts 4-methyl-2-pentanone are stirred and refluxed overnight with a water separator. After cooling to room temperature, water is added and the layers are separated. The organic layers are dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol, and 1-{3-[4-(di-phenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro- 2H-benzimidazol-2-one with melting point 153°C.

Example 17

By following the procedure in ex. XXXVIII and using equivalent amounts of the appropriate starting materials, the following compounds are prepared: 1-12-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}ethyl -1,3-dihydro-2H-benzimidazol-2 -one hemihydrate with melting point 131.5 oC;

1-{2-[4-(diphenylmethyl)-1-piperazinyl]ethyl}-1,3-dihydro-2H-benzimidazol-2-one of melting point 218°C; and 1-3-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}propyl-1,3-dihydro-2H-benzimidazol-2-one with melting point 198°C.

Example 1 8

A mixture of 4.8 parts 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 6.1 parts 4-(diphenylmethoxy)piperidine hydrochloride, 7.5 parts sodium carbonate and 200 parts 4-methyl-2-pentanone is stirred and refluxed overnight with a water separator. The reaction mixture is cooled and water is added. The layers are separated and the 4-methyl-2-pentanone phase is dried, filtered and evaporated. The oily residue is purified by column chromatography over silica gel using trichloromethane and 5% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, and 4.2 parts or 48% of 1-{3-[4-(diphenylmethoxy)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazole- 2-one with melting point 149.2°C.

In the same way, it was produced:

Claims (1)

1. Analogy method for the preparation of therapeutically active compounds of the formula: and pharmaceutically acceptable acid addition salts thereof, in which formula: Ar 1 and Ar 2 are each independently selected from phenyl, substituted phenyl and pyridinyl, wherein said substituted phenyl is phenyl with from 1-2 substituents independently selected from halogen, lower-alkyl, lower-alkoxy and nitro; m is an integer equal to 0 or 1; A is chosen among provided that when A is then m is zero and when A is then m=l; n is an integer from 2 to 6, provided that when Cn<H>2n represents a branched alkylene chain then at least 2 carbon atoms are present in the linear portion of the chain connecting B to the piperidine or piperazine nitrogen atom; and B is selected from: a) a residue of the formula: wherein R 1 and R 2 are independently selected from hydrogen, halogen, lower alkyl and trifluoromethyl; and Y is selected from oxygen, sulfur and a substituted nitrogen of the formula ^N-L wherein L is selected from hydrogen, lower-alkyl, lower-alkylcarbonyl, lower-alkoxycarbonyl-lower-alkyl, carboxy-lower-alkyl, phenyl, phenylmethyl, lower -alkylaminocarbonyl, hydroxymethyl and lower-alkynyl provided that when Y is 0 or 12 12 S R and R are hydrogen, Ar and Ar are both phenyl, A equals N and n equals 3 and; b) a residue with the formula: wherein: R and R are independently selected from hydrogen, halogen, lower alkyl and trifluoromethyl; and M is selected from hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, lower alkylthio, amino, lower alkylcarbonylamino, lower alkyloxycarbonylamino and cycloalkyl with from 3-6 carbon atoms, characterized by) to react a suitable reactive ester with the formula: wherein B<1> has the same meaning as B above, but different from 2-amino-1H-benzimidazol-1-yl of the formula: and W is a suitable reactive ester function derived from the corresponding alcohol, with a compound of the formula: preferably in the presence of a reaction-inert organic solvent and a suitable base, and at elevated temperatures to produce a compound of the formula: or b)' decarboxylation of a compound of the formula: under hydrolytic conditions to produce a compound of the formula: or c) cyclization of a compound of the formula: with a suitable cyclizing agent known per se in a manner known per se to prepare a compound of the formula: or wherein M' is hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, amino, lower alkyloxycarbonylamino or cycloalkyl, by reacting (IV) with a suitable cyclizing agent or d) removing a protecting group P by conventional methods from a compound with the formula: to prepare a compound of the formula: or e) acylating a suitable compound of formula (I-a) as set forth above by standard N-acylation procedures to produce a compound of formula: or f) introducing the group L<1-> in ways known per se into ■ a compound of the formula (I-c) as indicated above to produce a compound of the formula: wherein L' is selected from lower-alkyl, lower-alkylcarbonyl, lower- • . alkyloxycarbonyl^lower-alkyl, carboxy-lower-alkyl, phenylmethyl, -lower-alkylaminocarbonyl, hydroxymethyl and lower-alkenyl, provided that the unsaturated bond in said lower alkenyl is different from in a-positions, or g). condensation of a compound with the formula: with a suitable reactive ester of the formula: wherein W is as defined above, preferably in the presence of a reaction-inert organic solvent and a suitable base and at elevated temperatures, to prepare a compound of the formula: and, if desired, preparing pharmaceutically acceptable acid addition salts of the products from steps a to g.