DERIVATIVES

Background of the invention

In EP-A-0,363,963, published April 18, 1990, there are described some carbonyl and hydroxymethylene-benzimidazoles useful as antihistaminics. In US-4,695,575; US-5,041,448; US-4,943,580; US-4,988,689 and US-5,008,268 there are disclosed methylenebenzimidazole and methyleneimidazopyridine derivatives useful as antihistaminics and serotonin antagonists.

Description of the invention

The present invention is concerned with novel 4-piperidinyl derivatives having the formula :

the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein

=A ¹ -A ² =A ³ -A ⁴ = is a radical having the formula

wherein one or two hydrogen atoms in said radicals (a-1) to (a-7) may each independently be replaced by halo, Ci-6alkyl, Ci^alkyloxy, hydroxy ortrifluoro- methyl;

R ¹ is Ar or a radical of formula -D-R ² wherein D is O or S; R ² is Ci-βalkyl optionally substituted with hydroxy, Ci- alkyloxy, carboxyl or Ci^alkyloxycarbonyl; m is 1, 2, 3 or 4; n is 0, 1 or 2 ; L is hydrogen; Ci^a-U yl; C3-^cycloalkyl; C3^alkenyl optionally substituted with aryl; C^alkylcarbonyl; Cx-.galkyloxycarbonyl; arylcarbonyl; arylC^alkyloxy- carbonyl; or a radical of formula :

Alk is Ci-6alkanediyl; R ³ is cyano, aryl or Het;

R ⁴ is hydrogen, aryl, Het or Ci-6alkyl optionally substituted with aryl or Het;

R ⁵ is hydrogen, aryl, Het or Ci-^alkyl optionally substituted with aryl or Het

R ⁶ is aryl ornaphthalenyl;

Y is O, S, NR ⁷ ; said R ⁷ being hydrogen, Ci^alkyl or Ci^alkylcarbonyl ; Z ¹ and Z ² each independently are O, S, NR ⁸ or a direct bond; said R ⁸ being hydrogen or Cι--6alkyl;

T is O, S or NR ⁹ ; said R ⁹ being hydrogen, Ci-^alkyl or cyano;

each Het is selected from pyridinyl optionally substituted with one or two substituents each independently selected from halo, amino, mono- and di(Cι^alkyl)amino, nitro, cyano, Ci^alkyl, Ci^alkyloxy and hydroxy; pyrimidinyl optionally substituted with one or two substituents each independently selected from halo, amino, Ci-6alkylamino, Ci-6alkyl and Cι--6alkyloxy; pyridazinyl optionally substituted with Ci^alkyl or halo; pyrazinyl optionally substituted with halo, amino or Ci^alkyl; thienyl optionally substituted with halo or Ci-6alkyl; fiiranyl optionally substituted with halo or Ci-^alkyl; pyrrolyl optionally substituted with Ci^alkyl; thiazolyl optionally substituted with Ci-ealkyl; imidazolyl optionally substituted with one or two substituents each independently selected from and nitro; 1,3,4-thiadiazolyl

optionally substituted with Ci^alkyl or amino; oxazolyl optionally substituted with Ci-^alkyl; 2,3-dihydro-l,4-benzodioxinyl optionally substituted with Ci-βalkyl or halo; 2-oxo-2H-l-benzopyranyl and 4-oxo-4H-l-benzopyranyl both being optionally substituted with Ci-βalkyl; 3,7-dihydro-l,3-dimethyl-2,6-dioxo-lH-purin-7-yl optionally substituted with C^galkyl; and a bicyclic heterocyclic radical of formula

10 wherein

X ¹ and X ² each independently are O or S ; each R ¹⁰ is hydrogen, Ci-δalkyl, arylCi-βalkyl, Cι^alkyloxyCι.-6alkyl, hydroxy-

Ci-6alkyl or Ci^alkyloxycarbonyl;

R ¹¹ is hydrogen, Ci^alkyl, hydroxy, mercapto, Ci-6alkyloxy, Ci-^alkylthio, halo or 15 Ci-6alkyloxycarbonylCi-6alkyl ;

G ¹ is -CH=CH-CH=CH-; -S-CH=CH- or -N=CH-NH- ;

G ² is -CH=CH-CH=CH-, -(CH ₂ ) -, -S-(CH ₂ ) ₂ -, -S-(CH ₂ ) ₃ -, -S-CH=CH-,

-CH=CH-O-, -NH-(CH ₂ ) ₂ -, -NH-(CH ₂ ) ₃ -, -NH-CH=CH-, -NH-CH=N-, 20 -NH-N=CH- or -NH-N=CH-CH ₂ -;

G ³ is -CH=CH-CH=CH-, -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH-,

-CH=CH-CH=N-, -N=CH-N=CH- or -CH=N-CH=N- ; G ⁴ is -CH=CH-CH=CH-, -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH-,

-CH=CH-CH=N-, -N=CH-N=CH- or -CH=N-CH=N- ;

25 wherein one or two hydrogen atoms in said radicals G ¹ , G ² , G ³ or G ⁴ may be replaced by or halo, when connected to a carbon atom; or by Ci^alkyl, Cι--6alkyloxycarbonyl or arylCi-^alkyl when connected to a nitrogen atom; and

X ^* r rQ — is a radical having the formula

each aryl is phenyl optionally substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, nitro, cyano, trifluoromethyl, Ci^alkyl, Ci^alkyloxy, Ci^alkylthio, mercapto, amino, mono- and di(Ci-6alkyl)amino, carboxyl, Ci^alkyloxycarbonyl and Ci-6alkylcarbonyl;

Ar is phenyl optionally substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, nitro, cyano, trifluoromethyl, Ci^alkyl, Ci-galkyloxy, Cι--6alkylthio, mercapto, amino, mono- and di(Cι--6aIkyl)amino, carboxyl, Ci^alkyloxycarbonyl and Ci^alkylcarbonyl; thienyl; halothienyl; fiiranyl optionally substituted with Ci^alkyl and/or hydroxyCi^alkyl; oxazolyl optionally substituted with Ci-^alkyl and/or hydroxyCi^alkyl; pyridinyl optionally substituted with Ci-^alkyl; pyrimidinyl; pyrazinyl; thiazolyl optionally substituted with Ci^alkyl; orimidazolyl optionally substituted with Cι-- ₆ alkyl.

The compounds of formula (I) wherein Het is substituted with hydroxy, mercapto or amino, may also exist in their tautomeric forms. Such forms although not explicitly indicated hereinabove, are intended to be included within the scope of the invention.

As used in the foregoing definitions halo is generic to fluoro, chloro, bromo and iodo; Cι-_5alkyl defines straight and branch chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, pentyl, hexyl and the like; Ci-ι ₂ alkyl defines Ci-όalkyl radicals as defined hereinabove and the higher homologs thereof having from 7 to 12 carbon atoms; C3^cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C3^alkenyl defines straight and branch chained hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms such as, for example, 2-propenyl, 3-butenyl, 2-buteπyl, 2-pentenyl, 3-pentenyI, 3-methyl-2-butenyl and the like; and the carbon atom of said Cs-όalkenyl being connected

to a nitrogen atom preferably is saturated; Ci-6alkanediyl defines bivalent straight and branch chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl,

1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof.

The pharmaceutically acceptable acid addition salts as mentioned hereinabove comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. Said salt forms can conveniently be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as inorganic acids, for example, hydrohalic acid, e.g. hydrochloric, hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopro- panoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy- 1 ,2,3-propanetri- carboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzene- sulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.

The term acid addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

The compounds of this invention may have several asymmetric carbon atoms in their structure. As usual, each of these chiral centers may be indicated by the stereochemical descriptors R and S. The stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be included within the scope of the invention.

Aryl as used in the definition of R3, R^ and R^, in particular is phenyl optionally substituted with halo, C^aUcyl, hydroxy or Cj.galkyloxy; aryl as used in the definition of R6 in particular is phenyl optionally substituted with halo.

Interesting compounds are those compounds of formula (I) wherein =A ¹ -A ² =A ³ -A ⁴ = is a radical of formula =CH-CH=CH-CH= (a-1).

More interesting compounds are those interesting compounds wherein X — Q — is

a radical having the formula C=CH — (d-1).

Preferred compounds comprise those compounds of formula 00 wherein =A ¹ -A ² =A3-A ⁴ = is aradical of formula =CH-CH=CH-CH= (a-1); R ¹ is halophenyl; m is 1; n is 1; L is hydrogen, Cι_ι ₂ alkyl or a radical of formula -Alk-R ³ (b-1); -Alk-Y-R ⁴ (b-2); or -Alk-Z ¹ -C(=T)-Z ² -R ⁵ (b-3), wherein R ³ is cyano, phenyl, Ci-ealkyloxyphenyl, 2,3-dihydro-l,4-benzodioxinyl or a bicyclic heterocyclic radical of formula

wherein R-" is C^alkyl; G ² is-CH=CH-CH=CH-, -(CH^-, -S-(CH*2) , -S-(CH ₂ ) ₃ - or -S-CH=CH-; R ⁴ is hydrogen or pyrimidinyl; Y is O orNH; R ⁵ is Ci^alkyl, aminophenyl or thiazolyl; Z ¹ and Z ² each independently are O, NH or a direct bond and T is O or S.

More preferred compounds are those preferred compounds wherein L is hydrogen, C^alkyl or a radical of formula -Alk-R ³ (b-1); -Alk-Y-R ⁴ (b-2); or -Alk-Z ¹ -C(=T)-Z ² -R ⁵ (b-3), wherein R ³ is Ci^alkyloxyphenyl or a bicyclic heterocyclic radical of formula

wherein R ¹ * is methyl; G ² is-CH=CH-CH=CH-, -(CH ₂ ) ₄ -, -S-(CH ₂ ) ₂ -, -S-(CH ₂ ) ₃ - or -S-CH=CH-; R ⁴ is hydrogen or 2-pyrimidinyl; Y is O or NH; R ⁵ is Ci^alkyl, 2-aminophenyl or 2-thiazolyl; Z ¹ is NH, Z ² is NH or a direct bond and T is O or S.

Further preferred compounds of formula (I) are the compounds of formula

wherein L is hydrogen or a radical of formula -Alk-OH, -Alk-R ³ (b-1), or -Alk-Z ¹ -C(=T)-Z ² -R ⁵ (b-3), wherein R ³ is Ci^alkyloxyphenyl or a bicyclic heterocyclic radical of formula

. wherein G ² is-CH=CH-CH=CH-, -(CH ₂ ) ₄ -, -S-(CH ₂ ) ₂ -, or -S-CH=CH-; R ⁵ is methyl or 2-thiazolyl; Z ¹ is NH, Z ² is NH or a direct bond and T is O or S.

10 The most preferred compounds of formula (I) are those further preferred compounds wherein L is hydrogen, 2-hydroxyethyl or a radical of formula

15 wherein G ² is -S-(CH ₂ ) ₂ -, -S-CH=CH-, -CH=CH-CH=CH-, or -(CH ₂ ) ₄ -.

The compounds of formula (I) wherein X-πrrQ — is a radical of formula (d-1), said compounds being represented by formula (I-a), can be prepared by dehydration of an intermediate of formula (II-a), in the presence of an acid. ^■ 20

(H-a) (I-a)

Similarly, the compounds of formula (I) wherein XrrrrQ — is a radical of formula

(d-2), said compounds being represented by formula (I-b) can be prepared by dehydration of an intermediate of formula (Ill-a) or (EQ-b) in the presence of an acid.

25

Suitable acids are for example (poly)phosphoric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid and the like. The compounds of formulae (I-a) and (I- b) may also be obtained by refluxing an intermediate of formula (Il-a), (Ill-a) or (IH-b) in hexamethylphosphoric triamide.

The compounds of formula (I) wherein X-rrrQ — is a radical of formula (d-3) ,

said compounds being represented by formula (I-c), can be obtained by reduction of a compound of formula (I-b) following art-known reduction procedures.

For example, the compounds of formula (I-b) can be reduced by catalytic hydrogenation in a suitable solvent, e.g. methanol or ethanol, in the presence of hydrogen and an appropriate catalyst, e.g. platinum-on-charcoal, palladium-on-charcoal, Raney nickel and the like, optionally at an increased temperature and/or pressure.

Some compounds of formula (I-c) may also be obtained by catalytic dehydroxylation of an intermediate of formula (Hl-a) or (Ul-b) following art-known procedures.

The compounds of formula (I) wherein L is other than hydrogen, said L being represented by lΛ and said compounds being represented by formula (I-d) can be prepared by H-alkylating a compound of formula (I) wherein L is hydrogen, said compound being represented by (I-e), with an alkylating reagent of formula (IN).

In formula (IV) and hereinafter W represents an appropriate leaving group such as, for example, halo, e.g. chloro, bromo and the like; or a sulfonyloxy group such as, for example, methanesulfonyloxy , 4-methylbenzenesulfonyloxy and the like.

Said N-alkylation reaction can conveniently be conducted in a reaction-inert solvent such as, for example, water, an aromatic hydrocarbon, an alkanol, a ketone, an ether, a dipolar aprotic solvent, or a mixture of such solvents. The addition of an appropriate base such as, for example, an alkali or an earth alkaline metal carbonate, hydrogen carbonate, alkoxide, hydride, amide, hydroxide or oxide; or an organic base, such as, for example, an amine may be utilized to pick up the acid which is liberated during the course of the reaction. In some instances the addition of an iodide salt, preferably an alkali metal iodide, is appropriate. Somewhat elevated temperatures and stirring may enhance the rate of the reaction. Additionally, it may be advantageous to conduct said N_-alkylation under an inert atmosphere such as, for example, oxygen-free argon or nitrogen. Alternatively, said £J-alkylation may be carried out by applying art-known conditions of phase transfer catalysis reactions.

The compounds of formula (I-d) wherein L ¹ is Ci-πalkyl, C3-6cycloalkyl, a radical of formula (b-1), (b-2) or (b-3), said radicals being represented by the radical L-^H- and said compounds by formula (I-d-1) can also be prepared by the reductive J^-alkylation reaction of (I-e) with an appropriate ketone or aldehyde of formula L^=O (V), said 1-2=0 being an intermediate of formula L ² H2 wherein two geminal hydrogen atoms are replaced by =O, and L-2 is a geminal bivalent radical comprising Ci-I2alkylidene, C3-6cycloalkylidene, R ³ -Ci-6alkylidene, R ⁴ -Y-Ci-6alkylidene and R ⁵ -Z ² -C(=T)-Z ¹ -Ci-6alkylidene.

Said reductive N-alkylation reaction may conveniently be carried out by reducing a mixture of the reactants in a suitable reaction-inert solvent following art-known reductive N-alkylation procedures. In particular, the reaction mixture may be stirred and/or heated in order to enhance the reaction rate. Suitable solvents are, for example, water; Ci^alkanols, esters, ethers, halogenated hydrocarbons, dipolar aprotic solvents, carboxylic acids, or a mixture of such solvents. The term "art-known reductive N-alkylation procedures" means that the reaction is carried out either with sodium cyanoborohydride, sodium borohydride, formic acid or a salt thereof, e.g. ammonium formate and the like reducing agents, or alternatively under hydrogen atmosphere, optionally at an increased temperature and/or pressure, in the presence of an appropriate catalyst such as, for example, palladium-on-charcoal, platinum-on-charcoal and the like. In order to prevent the undesired further hydrogenation of certain functional groups in the reactants and the reaction products, it may be advantageous to add an appropriate catalyst-poison to the reaction mixture, e.g., thiophene, quinoline-sulphur and the like. In some instances it may also be advantageous to add an alkali metal salt to the reaction mixture such as, for example, potassium fluoride, potassium acetate and the like salts.

Reductive N-alkylation of a compound of formula (I-b) wherein L is hydrogen, said compounds being represented by (I-b-1), with an appropriate ketone or aldehyde of formula L-^O (V) under a hydrogen atmosphere and in the presence of an appropriate catalyst, but in the absence of an appropriate catalyst-poison, yields a compound of formula (I-c-1), wherein L-^H represents Ci-i2alkyl, C3- ₆ cycloalkyl or a radical of formula (b-1 ), (b-2) or (b-3).

σ-c-i)

The compounds of formula (I) wherein L is a radical of formula l C2-6alkanediyl, said and said compounds being represented by formula (I-d-2), may also be prepared by the addition reaction of a compound of formula (I-e) to an appropriate alkene of formula (NI).

(I-d-2)

The compounds of formula (I) wherein L is 2-hydroxyC2-6alkyl or a radical of formula (b-4), said compounds being represented by formula (I-d-3), can be prepared by reacting a compound of formula (I-e) with an epoxide (VII) wherein R* ² is hydrogen, Cι_4alkyl or a radical R ⁶ -O-CH2-.

The reaction of (I-e) with respectively (VI) and (VII) may be conducted by stirring and, if desired, heating the reactants in a reaction-inert solvent such as, for example, a ketone, e.g., 2-propanone, 4-methyl-2-pentanone, an ether, e.g., tetrahydrofuran, l,l'-oxybisethane, an alcohol, e.g., methanol, ethanol, 1-butanol, a dipolar aprotic solvent, e.g., N,N-dimethylformamide, N_,N-dimethylacetamide and the like.

The compounds of formula (I) can also be prepared by N.-alkylating an intermediate of formula (VIII) with an appropriate alkylating reagent of formula (IX).

(vm) ©

Said N-alkylation is conveniently conducted following art-known N-alkylation procedures as described hereinabove for the preparation of (I-d) from (I-e) and (IV).

The compounds of formula (I) wherein L is a radical of formula (b-2) and R^ is aiyl or Het, said R^ being represented by R ⁴ " ^a and said compounds by formula (I-d-4) may ^• also be prepared by alkylating a compound of formula (I) wherein L is a radical of formula (b-2) and R^ is hydrogen, said compound being represented by formula (I-d-5), with a reagent of formula (X-a) .

^~ 4 )

Similarly, the compounds of formula (I-d-4) may also be prepared by treating a compound of formula (XI) with a reagent of formula (X-b).

σ- - )

The alkylation reactions of (I-d-5) with (X-a) and (X-b) with (XI) may conveniently be conducted in an inert organic solvent such as, for example, an aromatic hydrocarbon, a ketone, an ether, an alcohol, or a dipolar aprotic solvent The addition of an appropriate base such as, for example, an alkali metal carbonate or hydrogen carbonate, sodium hydride or an organic base may be utilized to pick up the acid which is liberated during the course of the reaction. Somewhat elevated temperatures may enhance the rate of the reaction.

The compounds of formula (I) wherein L is a radical of formula (b-3), Z ¹ is NH, Z ² is other than a direct bond and T is other than NR ⁹ , said Z ² and T being represented by Z ^2_a and T ² , and said compounds by (I-d-6), can be prepared by reacting an isocyanate (T ² = O) or isothiocyanate (T ² = S) of formula (XDI) with a reagent of formula (XII).

l-ά-6)

The compounds of formula (I) wherein L is a radical of formula (b-3), Z ² is NH, Z* is other than a direct bond and T is other than NR ⁹ , said Z ¹ and T being represented by z!-a and T ² , and said compounds by (I-d-7), can be prepared by reacting an isocyanate (T ² = O) or isothiocyanate (T ² = S) of formula (XIV) with a compound of formula

The reaction of (XII) with (XIII), or (XIV) with (I-d-8) can generally be conducted in a suitable reaction-inert solvent such as, for example, an ether, e.g., tetrahydrofuran and

the like, a halogenated hydrocarbon, e.g., trichloromethane and the like. Elevated temperatures may be suitable to enhance the rate of the reaction.

The compounds of formula ^~ ) wherein L is a radical of formula (b-3), Z ² is a direct bond, Z ¹ is other than a direct bond and T is other than NR ⁹ , said Z*^ and T being represented by Z*- ^*~a and T ² , said compounds being represented by (I-d-9), can be prepared by reacting a compound of formula (I-d-8) with a reagent of formula (XV) or a reactive functional derivative thereof.

The reaction of (XV) with (I-d-8) may generally be conducted following art-known esterifϊcation or amidation reaction procedures. For example, the carboxylic acid may be converted into a reactive derivative, e.g., an anhydride or a carboxylic acid halide, which subsequently is reacted with (I-d-8); or by reacting (XV) and (I-d-8) with a suitable reagent capable of forming amides or esters, e.g., N,N-methanetetraylbis- [cyclohexamine], 2-chloro-l-methylpyτidinium iodide and the like. Said reactions may most conveniently be conducted in a suitable solvent such as, for example, an ether, e.g., tetrahydrofuran, a halogenated hydrocarbon, e.g., dichloromethane, trichloromethane, a dipolar aprotic solvent, e.g. N,N-dimethylformamide, and the like. The addition of a base such as, for example, N,N-diethylethanamine and the like may be appropriate.

The compounds of formula (I) wherein R3, R^ or R-5 are Het, may also be prepared following art-known procedures for preparing heterocyclic ring systems or following analogous methods. A number of such cyclization procedures are described in for example, US-4,695,575 and in the references cited therein, in particular US-4,335,127; US-4,342,870 and US-4,443,451.

The compounds of formula (I) can also be converted into each other following art- known procedures of functional group transformation. Some examples of such procedures are cited hereinafter. The compounds of formula (I) containing a cyano substituent can be converted into the corresponding amines by stirring and, if desired, heating the starting cyano compounds in a hydrogen containing medium in the presence of an appropriate catalyst such as, for example, platinum-on-charcoal, Raney nickel and the like catalysts. Suitable solvents are, for example, methanol, ethanol and the like. The compounds of formula (I) containing an amino group can also be obtained by hydrolysis of the corresponding carbamate derivative in acidic medium. Amino groups may be alkylated or acylated following art-known procedures such as, for example, M-alkylation, N-acylation, reductive _N[-alkylation and the like methods.

In all of the foregoing and in the following preparations, the reaction products may be isolated from the reaction mixture and, if necessary, further purified according to methodologies generally known in the art

Some intermediates and starting materials in the foregoing preparations are known compounds which may be prepared according to art-known methodologies of preparing said or similar compounds. For example, the preparation of hydroxymethylene intermediates similar to those of formula (Il-a) is described in EP-A-0,363,963, published April 18, 1990.

The intermediates of formula (VIII) can be prepared by reacting a compound of formula (XVI) with a piperidinyl derivative of formula (XVII) wherein R ¹³ represents cyano, trichloromethyl or a radical of formula -C(=R ¹⁴ )-OR ¹⁵ , wherein R ¹⁴ is O, S or NH and R ¹⁵ is Ci^alkyl.

(vm)

The intermediates of formula (Il-a), (Ill-a) and (Ill-b) may be obtained by

H-alkylating the intermediates of formula (Il-a), (I-Q-a) and (Ill-b) wherein L is hydrogen, said intermediates being represented by (II-a-1), (III-a-1) and (IH-b-1)

respectively, following similar procedures as described for the preparation of the compounds of formula (I-d).

The intermediates of formula (Il-a), (Ill-a) and (IH-b) wherein L is hydrogen and n is 1, said intermediates being represented by (II-a-2), (ϋI-a-2) and (HI-b-2), can be obtained from reduction of the pyridine ring of a compound of formula (XVIE-a), (XVm-b) and (XVIII-c), respectively.

(xvm-a) (π-a-2)

(xvm<) θπ-b-2)

For example, the intermediates of formula (XVHI-a), (XVTJI-b) and (XVIII-c) can be reduced by catalytic hydrogenation in a suitable solvent e.g. methanol, ethanol, or acetic acid, in the presence of hydrogen and an appropriate catalyst, e.g. rhodium-on-charcoal and the like, optionally at an increased temperature and/or pressure. Alternatively, said compounds of formula (XNQI-a), (XNπi-b) and (XVIII-c) may be reduced by an alkali metal in liquid ammonia, preferably in the presence of an alcohol (Birch reduction).

The intermediates of formula (XVTfl-a) and (XVEH-b) can be prepared by reacting a compound of formula (XLX), wherein R ¹⁶ is H or methyl, with an intermediate of formula (XX) in the presence of a base, in a reaction-inert solvent

^ TO _R ι* _{= H : (} χvm^)

R ¹⁶ = CH ₃ : (XVπi-b)

Suitable bases are, for example, potassium tert butoxide, n. butyllithium, sodium amide, sodium hydride or lithium diisopropylamide. Reaction-inert solvents are, for example, ethers, e.g. tetrahydrofuran, 1,4-dioxane and the like.

The intermediates of formula (XX) can be prepared by catalytic hydrogenolysis of the halo compound of formula (XXI), in a suitable solvent e.g. methanol or ethanol, in the presence of hydrogen and an appropriate catalyst, e.g. platinum-on-charcoal, palladium- on-charcoal and the like, and in the presence of a suitable base, e.g. calcium oxide, calcium carbonate and the like, optionally at an increased temperature and/or pressure.

(XXD (XX) The intermediates of formula (Il-a), (IH-a), (Ill-b) and (VIE) can also be converted among themselves following art-known procedures of functional group transformation as described hereinbefore for the compounds of formula (I).

The intermediates of formula (III-a-2) wherein m, R ¹ and =A ¹ -A ² =A ³ -A = are as defined under formula (I) are novel. The intermediates of formula (III-a-2) wherein m is 1, R ¹ is halophenyl and =A ¹ -A ² =A ³ -A = is =CH-CH=CH-CH= are especially developed for the preparation of the compounds of formula (I-b) and (I-c).

Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereoisomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like; and enantiomers may be separated from each other following art-known resolution methods, for example, by the selective crystallization of their diastereomeric salts with chiral acids. Pure

stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reactions occur stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereoselective methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

The compounds of formula (I), the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof possess useful pharmacological properties. More particularly, they are active antihistaminics which can clearly be demonstrated by, e.g. the results obtained in the test "Protection of Rats from Compound 48/80-induced lethality". Surprisingly, some of the present compounds have improved anti-histaminic activity over structurally related compounds wherein X^π Q — is CH— CH ₂ — ,

known from, e.g. EP-A-0, 151,826, published August 21, 1985, and US-4,695,575.

In view of their antihistaminic properties, the compounds of formula ( ) and their acid addition salts are very useful in the treatment of allergic diseases such as, for example, allergic rhinitis, allergic conjunctivitis, chronic urticaria, allergic asthma and the like.

In view of their useful antihistaminic properties the subject compounds may be formulated into various pharmaceutical forms for administration purposes. To prepare the antihistaminic compositions of this invention, an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.

Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and die like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to die skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. Acid addition salts of (I) due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

The present invention also relates to a method of treating warm-blooded animals suffering from said allergic diseases by administering to said warm-blooded animals an antiallergically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt form thereof.

Those of skill in treating allergic diseases in warm-blooded animals could easily determine the effective amount from the test results presented hereinafter. In general it is contemplated that an antiallergically effective amount would be from about 0.001 mg/kg to about 20 mg/kg body weight and more preferably from about 0.01 mg kg to about 5 mg/kg body weight.

The following examples are intended to illustrate and not to limit the scope of the present invention in all its aspects. Unless otherwise stated all parts therein are by weight.

Experimental art A. Preparation of the intermediates Example 1

100 Parts of polyphosphoric acid were stirred and heated in an oil-bath at 140°C. There were added 7.8 parts of 1,2-benzenediamine and dropwise 21.5 parts of ethyl

[l-(phenylmethyl)-4-piperidinylidene]acetate. After 30 min, the reaction mixture was cooled to 80°C, diluted with 200 parts of water and basified to pH 10 with NaOH 20%. The product was extracted with 4-methyl-2-pentanone and die extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CHCI3 / CH3OH(NH3) 95:5). The eluent of the desired fraction was evaporated, yielding 2.13 parts (9.7%) of 2-[[l-(phenylmethyl)-4- piperidinylidene]methyl]-lH-benzimidazole; mp. 186.4°C (interm. 1).

Example 2 a) A mixture of 10 parts of 2-chloro-l-[(4-fluorophenyl)methyl]-lH-benzimidazole, 3 parts of calciumoxide and 200 parts of methanol was hydrogenated at normal pressure and room temperature in the presence of 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in trichloromethane and this solution was washed witii water, dried, filtered and evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and petroleumether. The product was filtered off and dried, yielding 5.8 parts (67.6%) of l-[(4-fluorophenyl)methyl]-lIi- benzimidazole; mp. 6I.8°C (interm.2). b) To a stirred and cooled (-70°C) mixture of 15.7 parts of £f-(l-methylethyl)-2- propanamine and 63 parts of tetrahydrofuran there were added 61.9 parts of n.butyllithium in hexane 1.6M. After stirring for 15 min at -70°C, there was added dropwise a solution of 34.16 parts of intermediate (2) in 27 parts of tetrahydrofuran. Stirring at -70°C was continued for 1 hour and then there were added dropwise 18.2 parts of l-(4-pyridinyl)ethanone. The mixture was allowed to warm to room temperature and was poured into water. The crystallized product was filtered off, washed with acetonitrile and dried, yielding 26.5 parts (50%) of l-[(4-fluorophenyl)methyl]-α- methyl-α-(4-pyridinyl)-lH-benzimidazole-2-methanol; mp.228.5°C (interm. 3). In a similar way there was also prepared : l-[(4-fluorophenyl)methyl]-α-(4-pyridinyl)- lH-benzimidazole-2-methanol; mp. 160.6°C (interm. 4). c) A mixture of 25 parts of intermediate (3) and 500 parts of acetic acid was hydrogenated at normal pressure and 50°C in the presence of rhodium-on-charcoal

catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was diluted with water and neutralized with NH4OH. The product was extracted with trichloromethane and die extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CHCI3 / CH3OH(NH3) 95:5). The eluent of the desired fraction was evaporated and die residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 5.7 parts (23.7%) of l-[(4-fluorophenyl)methyl]-α- methyl-α-(4-piperidinyl)-lH-benzimidazole-2-memanol; mp. 183.4°C (interm. 5). In a similar way there was also prepared : 1 -[(4-fluorophenyl)methyl-α-(4-piperidinyl)- lH-benzimidazole-2-methanol; 208.9°C (interm. 6).

B. Preparation of the final compounds Example 3 A mixture of 2 parts of intermediate (5) and 15 parts of polyphosphoric acid was stirred for 1 hour at 150-160°C. After cooling to 100°C, the reaction mixture was carefully diluted with water. Next there was added NaOH (aq.) while cooling on ice. The product was extracted wit 4-methyl-2-pentanone and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CHCI ₃ / CH ₃ OH(NH3) 95:5). The eluent of the desired fraction was evaporated and die residue was converted into die (E)-2-butenedioate salt in ethanol. The salt was filtered off and dried, yielding 1 part (35.0%) of l-[(4- fluorophenyl)methyl]-2-[ 1 -(4-piperidinyl)-edιenyl]- lH-benzimidazole (E)-2-butenedioate (2:3); mp. 190.0°C (comp. 1). In a similar way there was also prepared : l-[(4-fluorophenyl)methyl]-2-(4-piperidinylidenemethyl)-lH-b enzimidazole ethanedioate(l:2) mp. 193.9°C (comp. 2).

Exam le 4

A mixture of 25 parts of compound (1) and 200 parts of methanol was hydrogenated at normal pressure and room temperature in the presence of 3 parts of palladium-on- charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and die filtrate was evaporated. The residue was purified by column chromatography (silica gel ; CHCI3 / CH3OH(NH3) 95:5). The eluent of the desired fraction was evaporated, yielding 16.5 parts (67%) of l-[(4-fluorophenyl)- methyl]-2-[l-(4-piperidinyl)ethyl]-lH-benzimidazole (comp. 3).

Example 5

To a stirred and cooled mixture of 4 parts of intermediate (1) and 45 parts of N^-dimethylformamide there were added 0.56 parts of a dispersion of sodium hydride in mineral oil (50%). After 1 hour there was added dropwise 1.9 parts of 1-chlσro- methyl-4-fluσrobenzene. Stirring was continued overnight at room temperature. The reaction mixture was poured into 4-metiιyl-2-pentanone and me whole was washed widi water (2x), dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 2.6 parts (53%) of l-[(4-fluorophenyl)methyl]-2-[[l-φhenylmedιyI)-4- piperidinylidene]medιyl]-lH-benzimidazole; mp. 104.9°C (comp.4).

Example 6

^• A mixture of 4.5 parts of ethyl (2-chloroethyl)carbamate, 10.05 parts of compound (1), 4.5 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone was stirred overnight at reflux temperature. The reaction mixture was diluted with water. The organic layer was separated, dried, filtered and evaporated, yielding 13.5 parts (99.8%) of ethyl [2-[4-[l-[l-[(4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]ed ιenyl]-l- piperidinyl]edιyl]carbamate (comp.5). The compounds listed in Table 1 were prepared in a similar way.

Table 1

* : (E)-2-butenedioate

The compounds listed in Table 2 were also prepared in a similar way but using N,N-dimethylacetamide instead of 4-medιyl-2-pentanone as a solvent.

Table 2

* : (E)-2-butenedioate

Example 7

A mixture of 3.35 parts of compound (1), 5 parts of formaldehyde 40% and 6 parts of formic acid was stirred for 4 hours at reflux temperature. After cooling, the reaction mixture was diluted widi water and neutralized with NaOH (aq.). The product was extracted with dichloromethane and die extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CHCI3 / CH3OH(NH3) 95:5). The eluent of the desired fraction was evaporated and the residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 0.7 parts

(20%) of l-[(4-fluorophenyl)methyl]-2-[l-(l-methyl-4-piperidinyl)ethe nyl]- 1H- benzimidazole; mp. 130.9°C (comp. 21).

Example 8 A mixture of 3.35 parts of compound (1), 1 part of polyoxymethylene and 120 parts of methanol was hydrogenated at normal pressure and room temperature in the presence of 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and die filtrate was evaporated. The residue was purified by column chromatography (silica gel ; CHCI3 / CH3OH(NH3) 95:5). The eluent of the desired fraction was evaporated and the residue was converted into die hydrochloride salt in 2,2'-oxybispropane by addition of 2-propanol saturated witii HCl. The salt was filtered off and dried, yielding 0.4 parts (9.0%) of l-[(4-fluorophenyl)- methyl]-2-[ 1 -( 1 -methyl-4-piperidinyl)ethyl]- lH-benzimidazole dihydrochloride monohydrate; mp. 167.7°C (comp. 22).

Example 9

Through a mixture of 2.4 parts of compound (2) and 40 parts of methanol there was bubbled oxirane for 5 min. The mixture was stirred for 15 min at room temperature, for 2 hours at 70°C (oxirane was bubbled dirough for another 10 min), and overnight at room temperature. The reaction mixture was evaporated and the residue was purified by column chromatography (silica gel ; CHCI3 / CH3OH(NH3) 95:5). The eluent of the desired fraction was evaporated and the residue was converted into die etiianedioate salt in ethanol. The product was filtered off and dried, yielding 1.6 parts (48%) of 4-[[l-[(4- fluorophenyl)methyl]- lH-benzimidazol-2-yl]methylene]- 1 -piperidineethanol ethane- dioate (1 :2); mp. 133.5°C (comp. 23).

In a similar manner there was also prepared :

4-[ 1 -[ 1 -[(4-fluorophenyl)methyl]- lH-benzimidazol-2-yl]ethenyl]- 1 -piperidineethanol

(E)-2-butenedioate (2:3); mp. 127.9°C (comp. 24).

Example 1Q

A mixture of 9 parts of compound (12) and 400 parts of methanol was hydrogenated at normal pressure and 20°C in the presence of 3 parts of Raney nickel. After the calculated amount of hydrogen was taken up, die catalyst was filtered off and die filtrate was evaporated, yielding 7.8 parts (89.1%) of 4-[l-[l-[(4-fluorophenyl)methyl]-lH.- benzimidazol-2-yl]ethyl]- 1 -piperidineedianamine (comp.25).

Exa ple ll

A mixture of 13.5 parts of compound (5) and 225 parts of hydrobromic acid 48% was stirred for 8 hours at 100°C. The reaction mixture was evaporated and die residue was taken up in water. The whole was neutralized witii NaOH (aq.) and extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated, yielding 11.6 parts (100%) of 4-[l-[l-[(4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]etheny l]-l- piperidineethanamine (comp.26). In a similar way there was also prepared :

4-[[l-[(4-fluorophenyl)rnethyl]-lH-benzimidazol-2-yl]meth ylene]-l-piperidine- ethanamine trihydrobromide hemihydrate (comp. 27).

Example 12

A mixture of 1.14 parts of 2-chloropyrimidine 3.78 parts of compound (26), 2 parts of sodium hydrogen carbonate and 80 parts of ethanol was stirred overnight at reflux temperature. The reaction mixture was evaporated and die residue was taken up in water. The product was extracted with 4-methyl-2-pentanone and die extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCI3 / CH ₃ OH 90:10). The eluent of die desired fraction was evaporated and die residue was converted into die (E)-2-butenedioate salt in a mixture of acetonitrile and etiianol. The product was filtered off and dried in vacuo at 100-110°C, yielding 1.4 parts (22%) of N-[2-[4-[l-[l-[(4-fluorophenyl)memyl]-lH-benzimidazol-2-yl]e dιenyl]-l-piperidinyl]- edιyl]-2-pyrimidinamine (E)-2-butenedioate (2:3); mp. 156.0°C (comp.28). In a similar way there was also prepared : N-[2-[4-[l-[l-[(4-fluorophenyl)memyl]-lH-benzύrύdazol-2-yl ]edιyl]-l-piperidinyl]- ethyl]-2-pyrimidinamine sesquihydrate; mp. 66.9°C (comp. 29).

Example 13

A mixture of 1.3 parts of 2-thiazolecarboxylic acid, 2.55 parts of 2-chloro-I-methyl- pyridinium chloride, 2.02 parts of M-ϋ-diethyledianamine and 130 parts of dichloromethane was stirred for 1 hour. There was added a solution of 3.65 parts of compound (27) in 65 parts of dichlorometiiane and stirring was continued for 1 more hour. The reaction mixture was washed witii water (2x), dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CHCI3 / CH3OH(NH3) 95:5). The eluent of die desired fraction was evaporated and the residue was converted into the (E)-2-butenedioate salt in etiianol. The product was filtered off and dried, yielding 1.1 parts (18%) of jV-[2-[4-[[l-[(4-fluorophenyl)methyl]-lH-benzimidazol-2- yl]π--ethylene]-l-piperidinyl]ethyl]-2-dτiazolecarboxamide (E)-2-butene-dioate (1:1); mp. 168.5°C (comp. 3.0).

Exaropig 14

To a stirred mixture of 1.7 parts of 2H-3,l-benzoxazine-2,4(lH)-dione and 22.5 parts of iLN-dimethylformamide there was added dropwise a solution of 4 parts of compound (25) in 22.5 parts of N_,H-dime&ylformamide. Stirring was continued for 4 hours at 70°C. The reaction mixture was poured into water and die product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated and die residue was purified by column chromatography (silica gel ; hexane / CHCI3 / CH3OH 45:45:10). The eluent of the desired fraction was evaporated and die residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1 part

(20.0%) of 2-amino- -[2-[4-[[l-[(4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]eth yl]- l-piperidinyl]ethyl]benzamide; mp. 178.0°C (comp. 31).

Example 15 A mixture of 1.03 parts of isotiiiocyanatomethane, 3.6 parts of compound (27) and 90 parts of tetrahydrofuran was stirred for 6 hours at room temperature. The reaction mixture was evaporated and die residue was diluted witii water. The product was extracted with trichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CHCI ₃ / CH3OH 90:10). The eluent of the desired fraction was evaporated and the residue was converted into die cyclohexanesulfamate salt in 2-propanone. The product was filtered off and dried, yielding 2 parts (20%) of ϋ-[2-[4-[[l-[(4-fluorophenyl)methyl]-lH-benzimidazol-2- yl]methylene]-l-piperidinyl]edιyl]-iϊ'-methyldιiourea cyclohexanesulfamate (1:3); mp. 156.4°C (comp. 32).

C. Pharmacological example Example 16

The useful antihistaminic properties of the compounds of formula (I) can be demonstrated in die test "Protection of rats from compound 48/80-induced lethality", which is described in US-4,556,660. The ED^-value (in mg kg) for the compounds 2;

6; 15; 18; 19; and 23 was found to range from 0.01 mg/kg to 0.04 mg/kg.

D. Composition Examples

The following formulations exemplify typical pharmaceutical compositions in dosage unit form suitable for systemic or topical administration to warm-blooded animals in accordance with the present invention.

"Active ingredient" (A.I.) as used diroughout these examples relates to a compound of formula (I), a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof.

Example 17 : Oral drops

500 g of the A.I. is dissolved in 0.5 1 of 2-hydroxypropanoic acid and 1.51 of the polyediylene glycol at 60~80°C. After cooling to 30~40°C there are added 351 of polyethylene glycol and die mixture is stirred well. Then there is added a solution of 1750 g of sodium saccharin in 2.51 of purified water and while stirring there are added 2.51 of cocoa flavor and polyethylene glycol q.s. to a volume of 501, providing an oral drop solution comprising 10 mg/ml of the A.I. The resulting solution is filled into suitable containers.

Example 18 : Oral solutions 9 g of metiiyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate are dissolved in 41 of boding purified water. In 3 1 of this solution are dissolved first 10 g of 2,3-dihydroxybutanedioic acid and thereafter 20 g of the A.I. The latter solution is combined widi the remaining part of the former solution and 121 of 1,2,3-propanetriol and 31 of sorbitol 70% solution are added tiiereto. 40 g of sodium saccharin are dissolved in 0.51 of water and 2 ml of raspberry and 2 ml of gooseberry essence are added. The latter solution is combined with die former, water is added q.s. to a volume of 201 providing an oral solution comprising 5 mg of the A.I. per teaspoonful (5 ml). The resulting solution is filled in suitable containers.

Example 19 : Capsules

20 g of the A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose, 0.8 g colloidal silicon dioxide, and 1.2 g magnesium stearate are vigorously stirred togetiier. The resulting mixture is subsequendy filled into 1000 suitable hardened gelatin capsules, each comprising 20 mg of the A.I..

Example 20 : Film-coated tablets

Preparation of tablet core

A mixture of 100 g of die A.I., 570 g lactose and 200 g starch is mixed well and tiiereafter humidified widi a solution of 5 g sodium dodecyl sulfate and 10 g polyvinyl- pyrrolidone (Kollidon-K 90®) in about 200 ml of water. The wet powder mixture is sieved, dried and sieved again. Then tiiere are added 100 g microcrystalline cellulose (Avicel®) and 15 g hydrogenated vegetable oil (Sterotex ®). The whole is mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of die active ingredient.

ga ing

To a solution of 10 g metiiyl cellulose (Metiiocel 60 HG®) in 75 ml of denaturated etiianol tiiere is added a solution of 5 g of ethyl cellulose (Ethocel 22 cps ®) in 150 ml of dichloromediane. Then there are added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol is molten and dissolved in 75 ml of dichloromethane. The latter solution is added to the former and then tiiere are added 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concen¬ trated colour suspension (Opaspray K- 1-2109®) and die whole is homogenated. The tablet cores are coated with die thus obtained mixture in a coating apparatus.

Example 21 : Iniectable solutions

1.8 g methyl 4-hydroxybenzoate and 0.2 g propyl 4-hydroxybenzoate are dissolved in about 0.51 of boiling water for injection. After cooling to about 50°C there are added while stirring 4 g lactic acid, 0.05 g propylene glycol and 4 g of the A. .The solution is cooled to room temperature and supplemented with water for injection q.s. ad 1 1 volume, giving a solution of 4 mg A.I. per ml. The solution is sterilized by filtration (U.S. P. XVII p. 811) and filled in sterile containers.

Example 22 : Suppositories 3 g A.I. is dissolved in a solution of 3 g 2,3-dihydroxybutanedioic acid in 25 ml polyethylene glycol 400. 12 g surfactant (SPAN®) and triglycerides (Witepsol 555®) q.s. ad 300 g are molten togetiier. The latter mixture is mixed well widi die former solution. The thus obtained mixture is poured into moulds at a temperature of 37-38°C to form 100 suppositories each containing 30 mg of the A.I.