NO145472B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1- (BENZAZOLYLALKYL) PIPERIDINE DERIVATIVES - Google Patents

Description

The present invention relates to an analogue method for the production of therapeutically active substances

A number of benzazolylalkyl-

and indolylalkyl-substituted piperidine derivatives, and a number of aminoalkyl-substituted benzazoles, some of which have pharmacological effects, in particular antidepressant, anticonvulsant, antihistamine or antispasmogenic effects.

Among other differences, the present compounds differ from such known substances by the nature of the respective benzazole and/or the substituted piperidine residue in the molecular structure.

A number of the previously known substances can be found in the following publications:

Int. Pharmacopsychiat 1°68 (l), page 214.

CA., 64, 2093b (1966). C. A., 72, 111466 (1970).

CA., 81, 120632b (1974).

In French Patent No. 2,042,321 (Derw. Fr.Week S 16, Pharm, p, 12), and

Belgian Patent No. 753|472.

The new 1-(benzazolylalkyl)piperidiri-derivatives which are prepared according to the present invention can be represented by the following structural formula

and their pharmaceutical acid addition salts,

where:

R 1 and R 2 independently of each other denote hydrogen, halogen, lower alkyl or trifluoromethyl,

B denotes the divalent groups

-N=N- and -N=CH-, where L denotes

hydrogen, lower, alkyl, lower alkanoyl or lower alkenyl,

and where said divalent radicals are connected to the benzene nucleus through their heteroatom,

R 3 denotes hydrogen or methyl,

m and n both denote a number' from 1 to 2 and

a) a group with formula

4 5 6

where R denotes hydrogen or lower alkyl, and R and R independently of each other denote hydrogen, halogen, lower alkyl or trifluoromethyl,

b) a group with formula

where R 7 M R 8 independently of each other denotes hydrogen halogen, lower alkyl or trifluoromethyl, Y denotes 0 or S, and the dashed line indicates that the double bond between the 3- and k-C atoms in the piperidine nucleus is optional, provided that when Y is equal to S there is a single bond between said 3- and 4-C atom in the piperidine nucleus and that said M is then hydrogen.

c) a group with formula

where R 9 denotes hydrogen, halogen, lower alkyl or trifluoromethyl and R"^ denotes hydrogen or halogen,

In the present context, the term "lower alkyl" means a straight-chain or branched carbon chain with 1 to 5 C atoms, e.g. methyl, ethyl, propyl, 1-methylethyl, butyl, pentyl and the like, "lower alkenyl" can be a straight-chain or branched alkenyl group with from 2 to 5 C atoms such as e.g. 1-methyl-ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and the like, and the term "halogen" denotes halogen atoms of atomic weight below 127, i.e. fluorine, chlorine, bromine or iodine.

The compounds are produced according to the invention in the following ways: a) Compounds with formula (I) which can be given the formula where R , R , R , m, n and have the meaning as previously indicated and B1 has the same meaning as B except for the meaning -NH-C -, is advantageously prepared by reacting a suitable reactive ester with formula (II), where X denotes a suitable reactive ester function derived from the corresponding alcohol, e.g. halogen, methanesulfonyl, 4-methylbenzenesulfonyl and the like, with a suitable piperidine derivative of formula (ill) where the -N^^X group has the meaning as above.

The above condensation reaction advantageously takes place in a suitable organic solvent such as e.g. a lower alkanol such as methanol, ethanol, propanol, butanol and the like, an aromatic hydrocarbon such as benzene, methylbenzene, dimethylbenzene and the like, a ketone such as 4-methyl-2-pentanone, an ether such as 1,4-dioxane, 1,1 *-oxybisethane and the like, N,N-dimethylformamide, nitrobenzene and the like. Addition of a suitable base such as an alkali metal or alkaline earth metal carbonate or hydrogen carbonate may be used to absorb the acid given off during the reaction. A small amount of suitable metal iodide, e.g. sodium or potassium iodide can be added as a reaction initiator, particularly when the reactive ester of formula (II) is a chloride. A somewhat elevated temperature is required to increase the reaction rate, and preferably the reaction takes place at the reflux temperature of the reaction mixture. In this and other processes, the reaction products from the mixture are worked up and, if necessary, purified using known methods. b) Compounds within the scope of formula (i), with formula, where R , R , m, n, R and -N A have meanings as before an-<12> m, n, <3></>"~~<\> an given can also be prepared u/ff^from corresponding compounds of formula (IV) where P is a suitable protecting group, by removing said protecting group in a known manner. Examples of such protection groups are i.a. lower alkyloxycarbonyl, 4-methylbenzenesulfonyl, methanesulfonyl and preferably a substituted ethenyl group of formula

where R and R can be different groups but where R for-12

stepwise is lower alkyl and R is preferably hydrogen, lower alkyl or phenyl.

When the protecting group is lower alkyloxycarbonyl, 4-methylbenzenesulfonyl or methanesulfonyl it can be easily removed

by alkaline hydrolysis, and when the protecting group is a substituted ethenyl group it is advantageously removed by acid hydrolysis of the suitable intermediate (IV). For the acid hydrolysis to remove the substituted ethenyl group from the compound (iv), many different protonic acids can be used, e.g. mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, and organic acids such as e.g. acetic acid, propanoic acid and the like. Furthermore, the turnover can take place in a reaction-inert

organic solvent which is usually used for hydrolytic reactions, e.g. methanol, ethanol, 2-propanone and the like.

c) Compounds within the scope of formula (i), and which have formula

12 3 S 'N

where R , R , m, n, R and -N A have the same meaning as before

2 \- -J ■ Q r

defined and B denotes _nh-C-, -NH-C- or -N=CH-,

can be prepared by ring-closing a suitable benzenediamine of formula (v), using a suitable ring-closing agent which directs

2

according to the nature of B in the desired product.

The above ring closure reaction can take place as is known in the field for the production of 1H-benzimidazoles, 1,3-dihydro-2H-benzimidazol-2-ones and 1,3-dihydro-2H-benzimidazol-2-thiones from 1,2-benzenediamines. Suitable ring-closing agents for O production of the compounds (i-c) where B 2 denotes -NH-C"-ex- e.g. urea, carbonyl dichloride and alkali metal isocyanates, and the ring-closing reaction can be carried out according to methods known in the field. For example, the desired compounds are easily obtained when urea is used as a ring closing agent by stirring and heating the reactants in the absence of any solvent.

When B 2 in the desired compounds (i-c) denotes ring closing agents such as e.g. carbon-

disulfide, thiourea, carbon thio-dichloride, ammonium thiocyanate and

similar and when B 2 denotes -N=CH-, formic acid or a suitable tri(alkyloxy)methane can be used as ring closing agent.

d) In a similar way as described above, compounds with formula can be prepared

123*78 X where R , R , R , R , R , m, n, B and Y have the meaning as indicated above by ring-closing suitable benzenediamines of formula (vi) with a suitable ring-closing agent. When carrying out this cyclization reaction, the same cyclization agent as described above can be used for the preparation of the compounds (i-c) from (v), more particularly for the preparation of the compound (i-c) where B 2betains respectively

e) Compounds where L is hydrogen are prepared by introducing L = lower alkyl or lower alkanoyl of known per se

manner.

If desired, the pharmaceutically acceptable acid addition salts of the products obtained under points a to e above can be prepared.

The starting materials used in the above-mentioned reactions can be prepared according to the procedure below.

Reactive esters of formula (II) of formula

12 3 2 where R , R , R , m, n, B and X have the meaning as previously indicated, can be prepared as follows: A suitably substituted 2-chloronitrobenzene of formula (Vill) is reacted with a suitable aminoalkanol (IX) by boiling the reactants under reflux in a suitable reaction-inert organic solvent such as e.g. a lower alkanol of the type ethanol, 2-propanol, butanol and the like, for the production of a /\ 2.-nitrophenyl)amino7alkanol of formula (x) which is then subjected to nitro-to-amine reduction, e.g. a catalytic hydrogenation with Raney nickel catalyst. The prepared /{2-amino-phenyl)amino/alkanol of formula (Xl) is then reacted with a ring-closing agent as described above for the preparation of compounds (i-c) from (v), and the produced alcohol (XII) is then reacted to the desired reactive ester (II-a) in a known manner.

Halides are advantageously prepared by reacting (XIl) with a suitable halogenating agent, such as e.g. sulfinyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus pentabromide, phosphoryl chloride and the like. When the reactive ester is an iodide, this is preferably derived from the corresponding chloride or bromide by replacing the halogen with iodine. Other reactive esters such as methanesulfonates and 4-methylbenzenesulfonates are prepared by reacting the alcohol with a suitable sulfonyl halide such as e.g. methanesulfonyl chloride and 4-methylbenzenesulfonyl chloride, respectively.

The above turnovers are more clearly illustrated by the following schematic equations. Intermediates of formula (II) having the formula

12 3

where R , R , R , m, n and X have meanings as previously indicated and

3

B denotes

where L<1> denotes lower alkyl, lower alkenyl or lower alkyl-carbonyl, can also be advantageously prepared by introducing a reactive ester side chain into a starting material of formula

in a manner known in the field. For example, one can first introduce a hydroxyalkyl chain by N-alkylating (XIII) with a suitable haloalkanol of formula (XIV) in a known manner by N-alkylation processes, forming an alcohol of formula (XV), whose hydroxyl group is then reacted with a reactive ester group as known in the field and as described previously. Instead of a haloalkanol ((XIV) you can also use a tetrahydro-2H-pyran-2-yl ether, and you then get the corresponding ether derivative of ( XV), where the ether group is split by acid hydrolysis, for example by stirring and heating the ether compound in dilute hydrochloric acid.

When the reactive ester (II-b) is a halide (II-b-I), it can alternatively be prepared by reacting (XIl) with one equivalent of a suitable dihaloalkane (XVl) in the presence of a suitable strong base such as e.g. sodium methanolate, or according to the Mackosza method with aqueous alkali and a quaternary ammonium catalyst, e.g. N,N,N-triethylbenzenemethanaminium chloride, which gives the desired intermediate (11-b-1).

The above procedure can be illustrated as follows:

Intermediate products with formula 12 3 where R , R , R , m, n and X have meanings as previously indicated can also be prepared by introducing the reactive ester side chain in a starting material of formula (XVIl)

where P denotes a suitable protecting group as indicated above, and then removes the protecting group from the product (XIX) in a known manner

manner in the area as previously described. The introduction of the reactive ester side chain can take place in a similar manner as described above for the introduction of the side chain in starting substances of formula (XIII). More specifically, one can first introduce a hydroxyalkyl chain whereupon the hydroxyl group in the produced intermediate (XVIII) is converted into a reactive ester group to produce (XIX), or when the reactive ester is a halide (XlX-a), the halide can be prepared directly by reacting ( XVII) with a suitable dihaloalkane. When the protective group P can be split off by alkaline hydrolysis, e.g. a lower alkyloxycarbonyl group, methanesulfonyl or 4-methylbenzenesulfonyl group, the N-alkylation reaction for introducing the respective hydroxyalkyl or haloalkyl chain should be carried out under non-hydrolytic conditions using e.g. a suitable metal base such as sodium hydride or sodium methanolate in a suitable aprotic organic solvent such as e.g. N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphorus triamide.

The above reactions are shown more clearly using the schematic equations below.

.V- l.lom products against formula 12 3 2 where R , R , R and X have meanings as previously indicated and L denotes lower alkyl or lower alkenyl, where the lower alkenyl group is unsaturated in the (3-, ^- or ^ -position can also be produced as follows:

A suitable intermediate of formula (II-c) wherein

m and n both denote 1, (lI-c-2) is treated with sodium metal in absolute ethanol to form a cyclic ether of formula (XX). This is then reacted with a suitable reactive ester L 2X, (XXl), where L and X have the meanings previously indicated, e.g. by boiling the reactants under reflux in a suitable organic solvent such as e.g. 2-propanone, for the production of the desired intermediate (il-d).

The compounds of formula (IV.) used as intermediates for the preparation of the compounds (l-b,) can generally be made by condensing an 'intermediate of formula (XIX) with a suitable intermediate of formula ((-ODII?) under similar conditions as 'described above for the preparation of the compounds (l-a) starting from and i(lll). Intermediates of formula (IV) where -~ N~*\ has the formula

and which is designated as (iv-b) can also be prepared by condensing a suitable reactive ester of formula (XIX) with a suitable N-(2-nitrophenyl)-4-piperidinamine of formula (XXII), followed by reduction of the nitro group in the prepared compound (XXIII) by usual nitro-to-amine reduction, e.g. by reacting the nitro compound with nascent hydrogen or by catalytic hydrogenation in the presence of a catalyst such as Raney nickel and ring closure of the formed benzenediamine (XXIV) with a suitable ring closing agent as described above.

These turnovers are illustrated by the following equation

The starting materials with formula (XXIl) can be prepared as described in US patent no. 3,910,930.

Intermediates of formula (v) are prepared by condensation of a suitable reactive ester of formula (XXV) with a suitable piperidine derivative of formula (lii), followed by reduction of the nitro group in the prepared intermediate (XXVI) to an amino group by conventional nitro- to-amine reduction.

The reactive esters of formula (XXV) used as starting material are easily produced from an alcohol of formula (x) by converting its hydroxyl group into a reactive ester group

in a known manner as described.

Intermediates of formula (Vi) can generally be prepared by condensation of a suitable reactive ester of formula (II) with a suitable N-(2-nitrophenyl)-4-piperidinamine of formula (XXII) and subsequent reduction of the nitro group in the product (XXVII) to an amine group by means of usual nitro-to-amine reduction as previously discussed.

It should be noted that when the nitro-to-amine reduction occurs by catalytic hydrogenation with palladium/activated carbon, dehalogenation can occur in compounds where aromatic halogen substituents are present.

Intermediates of formula (VII) can be similarly prepared by condensation of a reactive ester of formula (XXV) with a piperidine derivative of formula (XXIl) followed by reduction of both nitro groups in the product (XXVIII) in the usual manner as previously indicated . Starting substances with formula (ill), with the formulas

and methods for producing these can be found in the following publications:

a) US patent no. 3,238,216,

b) US Patent No. 3,161,645,

Belgian Patent No. 830,403,

c) US Patent No. 3,518,276 and

US Patent No. 3,575,990.

Starting substances with formula (ill) that have the formulas

can generally be prepared from a suitable N-(2-aminophenyl)-4-piperidineamine of formula

The starting materials (ill-d) are advantageously prepared by ring-closing (XXIX) with a suitable ring-closing agent such as carbon disulphide, and subsequent removal of the lower alkyloxycarbonyl group in the product (XXX) produced by alkaline hydrolysis.

The starting materials (ill-e) can be prepared by S-alkylating the compound (XXX) as described above, after which the lower alkyloxycarbonyl group in the product (XXXl) is removed.

N-(2-aminophenyl)~4-piperidinamines of formula (XXIX), which are known compounds, can be prepared according to methods described in US patent no. 3,910,930 and Belgian patent no. 830,403.

The above methods are evident from the following formulas

The starting materials for all the above reactions are generally known or they can be prepared in analogous ways.

For example, a preferred starting material of formula (XVIl) where P denotes a substituted ethenyl group, (XVII-a) of which a substantial part are known compounds, can be prepared as described in J.Chem.Soc., 1°60, page 308 and page 314. More particularly, such compounds are simply prepared by reacting a suitable ester of formula (XXXIl), where R <11> and R 12 have the meaning indicated above, with a suitable benzenediamine of formula (XXXIIl). This reaction advantageously takes place by stirring and boiling the reactants under reflux in a reaction-inert organic solvent while the water is removed azeotropically. Suitable reaction-inert organic solvents for this purpose can e.g. be aromatic hydrocarbons of the type benzene, methylbenzene, dimethylbenzene and the like.

Intermediates of formula (v), (Vi) and (Vil) are assumed

to be new and form part of the present invention to the extent that they are intermediates for the production of the desired compounds of formula (i).

The compounds according to the invention can be converted into therapeutically useful acid addition salts by treatment with an acid such as e.g. an inorganic acid of the hydrohalide acid type, such as hydrochloric acid, hydrobromic acid and the like, but also sulfuric acid, nitric acid, phosphoric acid and the like, or an organic acid such as e.g. Acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, propanedic acid, butanedioic acid, (x)-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-propenoic acid, α-hydroxybenzeneacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, k-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino- 2-hydroxybenzoic acid and similar acids. Conversely, the salt form can be transferred to the free base form by treatment with alkali.

Compounds of formula (i) and their therapeutically active acid addition salts have been shown to have strong antiemetic (antiemetic) activity, as demonstrated by the ability to block apomorphine-induced vomiting in dogs.

The method used has been described earlier by P.A.J. Janssen and C.J.E. Niemegeers in Arzneim.-Forsch. (Drug Res.) 9» 765-767 (1959).

The compounds listed below were administered subcutaneously to beagle dogs at various doses, and the animals were then exposed to a standard dosage of 0.31 mg/kg apomorphine (subcutaneous).

The table below gives ED^ values for a number of compounds that were considered. In the present sense, the EDj-Q value indicates the dose that protects 50% of the animals against vomiting.

It will be understood that the indicated compounds in the tables are not listed in order to limit the invention to these, but only to give examples of the outstanding antiemetic effects of all compounds falling within the scope of formula (i).

The following examples shall illustrate the preparation of intermediate products used in the method according to the invention. Unless otherwise stated, all quantities are by weight.

Example I

A mixture of 100 parts of 1-chloro-2-nitro-4-(trifluoromethyl)benzene, 90 parts of 3-amino-1-propanol and 200 parts of butanol is stirred and heated to reflux temperature. Reflux continues to be stirred overnight. The reaction mixture is cooled and evaporated. Water is added to the evaporation residue and the whole is acidified with hydrochloric acid solution. The product is extracted with methylbenzene. The extract is dried and filtered and evaporated. The solid evaporation residue is crystallized from petroleum ether. The product is filtered and dried to yield 141 parts. (100$) 3--£/2-nitro-k-(tri fluormety 1) f eny l/amino^f-l-propanol.

Example II

One repeats the procedure from example I and uses equivalent amounts of the pulping starting materials: and

poses:

3-(T4-methyl-2-nitrophenyl)amino7-1-propanol as residue, 3-(T4,5-dichloro-2-nitrophenyl)amino7-1-propanol, m.p. 97°C and 3-(T2-chloro-6-nitrophenyl)amino7-1-propanol as residue.

Example III

A mixture of 70 parts of 3-(X4-methyl-2-nitrophenyl)-amino7-1-propanol and 400 parts of methanol is hydrogenated at normal pressure and room temperature with 10 parts of palladium/activated carbon catalyst 10$. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated, yielding 54 parts (91$) of 3-^T2-amino-4-methylphenyl)amino7-1-propanol as evaporation residue.

Example IV

A mixture of 141 parts of 3-'£/^-nitro-4-(trifluoromethyl)-phenyl7amino7j-1-propanol and 1200 parts of methanol is hydrogenated at normal pressure and room temperature with 15 parts of Raney nickel catalyst. After absorption of an appropriate amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from 2,2*-oxybispropane to give 110 parts (100$) of 3-^/2-amino-4-(trifluoromethyl)phenyl7amino3r-1-propanol.

Example V

In a similar way as in example IV and with equivalent amounts of the suitable starting materials, the following are prepared: 3-[T2-amino-4,5-dichlorophenyl)amino7-1-propanol hydrochloride,

o

sm.p. + 185 C,

3-[X2-amino-6-chlorophenyl)amino7-l-propanol as evaporation residue and

3-((X2-amino-4-chlorophenyl)amino7-1-propanol as oily residue).

Example VI

To a stirred and cooled solution of 54 parts of 3-(X2-amino-4-methylphenyl)amino7-l-propanol in 30 parts of hydrochloric acid solution 10% and 200 parts of water is added dropwise a solution of 28 parts of potassium cyanate in 50 parts of water at a temperature below 10°C. The mixture is then stirred for 1 hour at room temperature and 24 hours at reflux temperature. After cooling to room temperature, the product is extracted with trichloromethane. The extract is washed with 5% hydrochloric acid solution, dried, filtered and evaporated. The evaporation residue is crystallized from 4-methyl-2-pentanone to give 19.5 parts (31$) of 1,3-dihydro-1-(3-hydroxypropyl)-

5-methyl-2H-benzyl i.dazol-2-one, m.p. ll4.1°C,

Ex empe l VII

In a similar way as in example VI and with equivalent amounts of the suitable starting materials, the following are prepared: 1,3-dihydro-1-(3-hydroxypropyl)-5-(trifluoromethyl)-2H-benzimidazol-2-one,

5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one, m.p. 174.7°C,

4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one,

and

5~chloro~lf 3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one, m.p. 148.8°C.

Example VIII

11.9 parts of N,N-diethylethanamine are added to a stirred solution of 18.5 parts of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one in 325 parts of dichloromethane. 11.5 parts of methanesulfonyl chloride are then added dropwise (slowly). Stirring is then continued for 1 hour at reflux temperature. After cooling, the reaction mixture is washed with water, dried, filtered and evaporated. The solid residue is crystallized from 4-methyl-2-pentanone to give 15 parts (58$) of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one-methanesulfonate, sm. p. 125°C.

Example IX

In a similar way as in example VIII and with equivalent amounts of the suitable starting materials, the following is prepared: 3-(5,6-dichloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl methanesulfonate which an oily residue,

3-(7-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl methanesulfonate and

3-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl methanesulfonate, m.p. + 140°C.

Example X

A mixture of 30 parts of 1H-benzimidazole, 4£) parts of 2-(4-chlorobutoxy)tetrahydro-2H-pyran, 21 parts of potassium hydroxide and 200 parts of ethanol is stirred and refluxed over the mixture. The reaction mixture is cooled to room temperature, filtered and the filtrate is evaporated. The evaporation residue is stirred in water and acidified with a dilute hydrochloric acid solution. The whole thing is stirred and heated for 30 minutes in a water bath. After cooling to room temperature, the product is extracted with methylbenzene. The water phase is separated and made alkaline with ammonium hydroxide. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated to give 50 parts of 1H-benzimidazole-1-butanol as an oily residue.

Example XI

To a stirred mixture of 23 parts of 1,3-dihydro-1-(3-hydroxypropyl)-5-(trifluoromethyl)-2H-benzimidazol-2-one in

150 parts of trichloromethane are added dropwise to 32 parts of sulfinyl chloride. The whole is then heated to reflux and stirring is continued for 1 hour at reflux temperature. After cooling, the reaction mixture is evaporated and the residue is crystallized from 2,2'-oxybispropane which gives 1 part (56%) 1-(3-chloropropyl)-1,3-dihydro-5-(trifluoromethyl)-2H-benzimidazol-2-one.

Example XII

In the same way as in example XI and with an equivalent amount of suitable hydroxy compound as starting material, the following chlorides are prepared: 5-chloro-1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one,

6-chloro-1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one,

sm.p. 122°C, and

1-(^-Chlorobutyl)-1H-benzimidazole as an oily residue.

Example XIII

To a stirred and refluxing mixture of 35 parts of k-fluoro~1,2-benzenediamine in 270 parts of dimethylbenzene, a solution of 57 parts of ethyl-ct-acetylbenzene acetate in 90 parts of dimethylbenzene is added dropwise over the course of 2 hours while the water and ethanol formed are distilled off (water separator). The reaction mixture is evaporated and the evaporation residue is crystallized from 2-propanol. The product is filtered off and purified by column chromatography on silica gel with a mixture of trichloromethane and methanol (98:2 parts by volume) as eluent. The pure fractions are combined and the eluent evaporated to give 11 parts of 6-fluoro-1,3-dihydro-1-(1-methyl-2-phenylethenyl)-2H-benzimidazol-2-one, m.p. 190°C.

Example XIV

To a stirred solution of 8.5 parts of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one in 45 parts of N,N-dimethylformamide, 1.7 parts of sodium hydride dispersion 78 are added in portions $, After stirring for 1 hour at room temperature, the whole is cooled to 0-5°C and 8.65 parts of 1-bromo-3-chloropropane are added dropwise (slowly). Stirring is then continued for 3 hours at room temperature. The reaction mixture is poured onto crushed ice and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The evaporation residue is crystallized from 2-propanol to give 5.5 parts (44$) of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-(hn, m.p. .115°C.

Example XV

To a stirred and hot (55°C) mixture of 22.2 parts of 1,3-dihydro-5,6-dimethyl-3-(1-methyl-2-phenylethenyl)-2H-benzimidazol-2-one, 3 parts N,N,N-triethylbenzenemethanaminium chloride and 112.5 parts of sodium hydroxide solution 60$ are added dropwise to 15.8 parts of 1-b»om-3-chloropropane (slightly exothermic reaction). Stirring is then continued for 5 hours at 55<*>0. After cooling, water is added and the paste-like product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2•-oxybispropane and, after drying, gives 25 parts (88.5$) of 1-(3-chloropropyl)-1,3-dihydro-5,6-dimethyl-3-(1-methyl-2- phenylethenyl)-2H-benzimidazol-2-one, m.p. 98°C.

Example XVI

In a similar manner as in Example XV and with equivalent amounts of the appropriate starting materials, the following is prepared: 1-(3-chloropropyl)-1,3-dihydrob-3-(2-propenyl)-2H-benzimidazol-2-one as a residue,

1-(3-chloro-2-methylpropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one as evaporation residue, and

1-(3-chloropropyl)-5-fluoro-1,3-dihydro-3-(1-methyl-2-phenylethenyl)-2H-benzimidazol-2-one as an oily residue.

Example XVII

A solution of 13 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one in 6 parts of hydrochloric acid solution and 40 parts of ethanol is stirred for 2 hours at room temperature . The reaction mixture is evaporated and the evaporation residue is crystallized from 2-propanol to give 9.5 parts (90$) of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, m.p.115°C.

Example XVIII

A mixture of 25 parts of 1-(3-chloropropyl)-1,3-dihydro-5,6-dimethyl-3-(1-methyl-2-phenylethenyl)-2H-benzimidazol-2-one, 165 parts of hydrochloric acid solution 6N and 160 parts of ethanol are stirred and boiled at reflux for 6 hours. The reaction mixture is evaporated and the residue is dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2<1->pxybispropane and 2-propanol and, after drying, gives 16 parts (94.7$) of 1-(3-chloropropyl)-1,3-dihydro-5,6-dimethyl- 2H-benzimidazol-2-one, m.p. l40°C.

Example XIX

A solution of 180 parts of 3-/'[2-nit.r6phenyl)amino7-1-propanol in 200 parts of methanol and 100 parts of hydrochloric acid solution ION is hydrogenated at normal pressure and 50°C in the presence of 5 parts of palladium/charcoal catalyst 10$. After absorption of the calculated amount of hydrogen (3 mol), the hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The residue (mainly 3-(X2-aminophenyl)amino7-1-propanol hydrochloride) is dissolved in 500 parts of water. A solution of 88.8 parts potassium isocyanate in 150 parts water is added to the solution and the whole is stirred and boiled at reflux for 15 hours. The reaction mixture is cooled and the product is extracted with trichloromethane. The extract is dried and evaporated. The residue is dissolved in 25o parts of boiling water, treated with activated charcoal and crystallized at room temperature. The precipitate is filtered off and recrystallized from 400 parts of water and then from ethyl acetate which gives 58 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-oneihydrate, m.p. 48-65°C.

63 parts of methanesulfonyl chloride are added dropwise to a solution of 52.5 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one hydrate in 200 parts of pyridine. The mixture is stirred and cooled in air for 2 hours. The pyridine is evaporated. 500 parts of water are added to the residue and the precipitate formed is filtered off. It is dissolved in 350 parts of trichloromethane. The solution is dried over magnesium sulphate and evaporated. The evaporation residue is crystallized from 40 parts of methylbenzene and gives 25.5 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one-methane-sulfonate, m.p. 118-120°C.

5.4 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one-methanesulfonate are added cold to a solution of 0.5 parts of sodium in kO parts of absolute ethanol. This is stirred until all solids have dissolved. The solution is stirred further and boiled at reflux for 2 hours. After cooling, the reaction mixture is filtered from some inorganic material and the filtrate is evaporated. The residue is dissolved in 80 parts of methylbenzene, boiled with activated carbon, filtered and the filtrate is re-evaporated. The solid residue is washed with cold methylbenzene and crystallized from 16 parts of methylbenzene which gives 2.6 parts of 3'4-dihydro-2H-[1,37Denz<_>imidazole, m.p. 116.5-118.5°C.

5.7 parts of iodomethane are added to a solution of 5.7 parts of 3,4-dihydro-2H-/1»37°xazino-/3,2-α7benzimidazole in 80 parts of 2-propanone and this is stirred at reflux for 2 hours and 50 minutes. A second portion of 5.7 parts of iodomethane is added and this is further stirred under reflux for 2 hours and 50 minutes. The solvent is evaporated to give 1,3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one as an oily residue.

Example XX

A mixture of 84 parts of ethyl 4-(X4-chloro-2-nitro-phenyl)-amino7-1-piperidine carboxylate and 750 parts of hydrobromic acid solution 48% in water is stirred at reflux for 4 hours.

The precipitated product is filtered off, washed with water and petroleum ether, dried to give 71 parts (81$) of N-(4-chloro-2-nitrophenyl)-4-piperidinamine hydrobromide, m.p. 275°C.

A mixture of 105 parts 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-behzimidazol-2-one, 71 parts N-(4-chloro-2-nitrophenyl)-4 -piperidinamine hydrobromide, 53 parts sodium carbonate, 0.2 parts potassium iodide and 320 parts 4-methyl-2-pentanone are stirred at reflux for 24 hours with water separators. The reaction mixture is cooled, water is added and the layers are separated.

The organic phase is dried, filtered and evaporated to give 98.5 parts (100$) of 1-[3-{4-[4-chloro-2-nitrophenyl)amino7-1-piperidinyl^-propyl7-1,3- dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one as residue.

A solution of 98.5 parts of 1-(3-[4-([4-chloro-2-nitro-phenyl)-amino7-1-piperidinyl]propyl7-1,3-dihydro-3-(1-methylethenyl)- 2H-benzimidazol-2-one in 36O parts of methylbenzene is acidified with 2-propanol which is previously saturated with gaseous hydrogen chloride. After boiling for a while, an oil falls out. The overlying phase is decanted off and the remaining oil is suspended in water. The suspension is made alkaline with concentrated ammonium hydroxide solution. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The entrapment residue is crystallized from 4-methyl-2-pentanone. The product is filtered and dried to give 68 parts (75.5$) of 1-(3-4-(4-chloro-2-nitrophenyl)amino7-1-piperidinyl3i-propyl7-1,3-dihydro-2H-benzimidazole-2 -on.

A mixture of 21.5 parts of 1-(3-{4-(4-chloro-2-nitro-phenyl)-amino7-1-piperidinyl]5-propyl7-1,3-dihydro-2H-benzimidazol-2-one and 240 parts of methanol are hydrogenated at normal pressure and at room temperature with 5 parts of Raney nickel. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated to give 20 parts (100$) of 1-(3--£4-(X2-amino-4-chlorophenyl)-amino7-1-piperidinyl^propyl7-1, 3-dihydro-2H-benzimidazol-2-one as evaporation residue.

Example XXI

A mixture of 21.5 parts of 1-(3-[4-(4-chloro-2-nitro-phenyl)amino7-1-piperidinyl-3-propyl7-1,3-dihydro-2H-benzimidazol-2-one and 240 parts of methanol is hydrogenated at normal pressure and room temperature with 10 parts palladium/charcoal catalyst 10$. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated to give 18.5 parts (100$) of l-(3-£4-(T2-aminophenyl)amino7-1-piperidinyl^-propyl7-1,3-dihydro- 2H-benzimidazol-2-one as evaporation residue.

Example XXII

To a stirred mixture of 39.2 parts of 3-(2-nitro-phenyl)~amino-l-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, heating is continued for 6 hours at reflux temperature. The reaction mixture is evaporated to give 43 parts ($100) of N-(3-chloropropyl)-2-nitrobenzenamine as an evaporation residue.

A mixture of 43 parts N-(3-chloropropyl)-2-nitro-benzenamine, 47.8 parts 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 30 .3 parts of N,N-diethylethanamine and 180 parts of N,N-dimethylacetamide are stirred and heated for 6 hours at 100°C. The reaction mixture is cooled and poured into 1500 parts of water. The precipitated product is filtered off, washed with water and with 2,2'-oxybispropane and dried to give 64 parts (78.3$) of 5-chloro-l,3-dihydro-l-£l-/3-(2- nitrof enylamino)-propyl7-4-piperidinyl J'-2H-

benzimidazol-2-one, m.p. 220°C.

A mixture of 64 parts of 5-chloro-1,3-dihydro-1-(2-nitrophenylamino)propyl-7-4-piperidinyl-2H-benzimidazol-2-one in 200 parts of methanol and 225 parts of tetrahydrofuran is hydrogenated at normal pressure and room temperature with 10 parts of Raney nickel catalyst. After absorption of the calculated amount of hydrogen, the catalyst is filtered from over "hyflo<*> and the filtrate is evaporated. Evaporation residue is crystallized from a mixture of 2-propanol and ethanol. The product is filtered off and dried to give 42 parts (70.5%) of 1-/1~£3-/N-(2-aminophenyl)amino7-propyl3;■z^-piperidinyl7-5-chloro-1,3-dihydro- 2H-benzimidazol-2-one, m.p. iQ6°C.

The following examples shall illustrate the invention in more detail.

Example 1

A mixture of 4.6 parts 1-(3-chloropropyl)-1,3-di-hydrp-2H-benzimidazol-2-one, 5 parts 1-(p-fluorophenyl)-1,3,8-triazaspiro/5 .57 decan-4-one, 10 parts sodium carbonate, 0.2 parts potassium iodide and 80 parts 4-methyl-2-pentanone are stirred at reflux overnight. After cooling, the precipitated product is filtered off and triturated twice: first in a boiling mixture of 4-methyl-2-pentanone and 2-propanol and then in boiling methanol. The product is filtered off again and crystallized from a mixture of N,N-dimethylformamide and water which gives 4.5 parts of 8-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl7-1 -(4-Fluorophenyl)-1,3,8-triazaspiro-[5,57decan-4-one, m.p. 215.4°C.

Example 2

In the same way as in example XXIII and with equivalent amounts of the starting materials in question, the following compounds are prepared: 8-(3-(6-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl7-1 -(4-Fluorophenyl)-1,3»8-triazaspiro/5,57decan-4-one hemihydrate, m.p. 233°C, 1-(4-fluorophenyl)-8-(3-(2,3-dihydro-5,6-dimethyl-2-oxo-1H-benzimidazol-1-yl)propyl7-1,3>8- triazaspiro/5, 57decan-4-one, m.p. 245.2°C,

8-[3-(2,3-dihydro-2-oxo-3-(2-propenyl)-1H-benzimidazol-1-yl7-propyl3-1-phenyl-1,3,8-triazaspiro[1,57decan-4] -on, sm.p. 114°C,

8-/3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl7-1-(3-(trifluoromethyl)phenyl7-1,3>8-triazaspiro/5,57decan-4- on, sm.p. 198.2°C,

8-(3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl7-1-phenyl-1,3,8-triazaspiro/5,57decan-4-one, m.p. 228°C, 8-[3-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-propyl7-1-(4-fluorophenyl)-1,3,8-triazaspiro /5.57decan-4-one, m.p. 171.7°C,

8-[3-(6-Chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-propyl7-1-phenyl-1,3,8-triazaspiro/5,57decan-4-one , sm.p. 255-256°C,

1-( 4-Fluorophenyl)-8-^3-(2*, 3-dihydro-2-oxo-5-(trifluoromethyl)-1H-benzimidazol-1-yl7-propyl2-1,3,8-triazaspiro/ 5,57-decan-4-one, m.p. 259.7°C,

8-(3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl7-3-methyl-1-phenyl-1,3,8-triazaspiro[1,57decan-4-one] sm.p. 186°C,

1_(4-chloro-3-methylphenyl)-8-(3-(2,3-dihydro-2-oxo-1H~benzimidazol-1-yl)propyl7-1,3»8-triazaspiro/4",57decane- 4-on, sm.p.

.208.6°C, and

8-[3-(1H-benzimidazol-1-yl)propyl7-1-phenyl-1,3,8-triazaspiro-[5,57decan-4-one, m.p. 191°C

Example 3

A mixture of 4.2 parts of 4-chloro-1,3-dihydro-§-(3-hydroxypropyl)-2H-benzimidazol-2-one-methanesulfonate, 2.5 parts of 1-phenyl-1,3»8-triazaspiro /5,57decan-4-one, 10 parts sodium carbonate and 80 parts 4-methyl-2-pentanone are stirred at reflux overnight. The reaction mixture is cooled and water is added. The precipitated product is filtered off and crystallized twice from a mixture of N,N-dimethylformamide and water to give 0.8 parts (17$) of 8-(3-(7-chloro-1,3-dihydro-2-oxo- 2H-benzimidazol-1-yl)-propyl7-1-phenyl-1,3,8-triazaspiro/5,57<d>ecan-4-one, m.p. 258?4°C.

Example 4

In a similar way as in example XXV and by carrying out the reaction in N,N-dimethylformamide as solvent, the following compounds are prepared from the relevant starting materials: 8-[3-(5-chloro-2,3-dihydro-2-oxo-1H- benzimidazol-1-yl)-propyl7-1-phenyl-1,3,3-triazaspiro/5,57decan-4-one, m.p. 233.7°C and 8-(3-(2,3-dihydro-5-methyl-2-oxo-1H-benzimidazol-1-yl)-propyl7-1-phenyl-1,3,8-triazaspiro /4", 57decan-4-one, m.p. 255, 5°C.

Example 5

A mixture of 5 parts 1,3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one, 3.4 parts 1-phenyl-1,3,8-triaza-spiro/^ ,57decan-4-one, 2.65 parts sodium carbonate and 22.5 parts N,N-dimethylformamide stirred and heated for 2 hours at 70 • oC. The reaction mixture is cooled and poured into water, whereupon an oily precipitate is obtained. The overlying water phase is decanted off and the remaining oil is dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is purified by column chromatography on silica gel with a mixture of trichloromethane and 5% methanol as eluent. The pure fractions are collected and the eluent is evaporated giving 1 part of 8-(1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl)propyl7-1-phenyl-1,3,8 -triazaspiro/5,57decan-4-one, m.p. l6k, k°C,

Example 6

A mixture of 8 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one-methanesulfonate, 9»2 parts of 1-phenyl-1,3»8-triazaspiro /5,57decan-4-one and 90 parts of N,N-dimethylformamide are stirred and heated at 60°C for 1 hour. The reaction mixture is evaporated and water is added to the evaporation residue. The whole is instilled alkaline with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The evaporation residue is purified by column chromatography on silica gel with a mixture of trichloromethane and 10% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is triturated in 4-methyl-2-pentanone. The product is filtered off and dried to give 2 parts of 8-(3-(5,6-dichloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl7-1-phenyl-1,3,8 -triazaspiro/5,57decan-4-one, m.p. 275.2°C.

Example 7

A mixture of 2.3 parts 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 2.5 parts 5-chloro-1,3-dihydro-1-(k-piperidinyl) -2H-benzimidazol-2-one, 3»2 parts sodium carbonate,

0.1 part potassium iodide and 80 parts 4-methyl-2-pentanone are stirred and boiled at reflux for 2k hours. The reaction mixture is cooled to room temperature and water is added. The undissolved product is filtered off and purified by column chromatography on silica gel with a mixture of trichloromethane and 10% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered and crystallized from a mixture of N,N-dimethylformamide and water to give 1.3 parts (30$) of 5-chloro-l--£l-/3-

(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl7-4-piperidinyl£-1,3-dihydro~2H-benzimidazol-2-one, m.p. 242.5°C.

Example 8

In a similar manner as in example XXIX and with equivalent amounts of the suitable starting materials, the following compounds are prepared: oxo-1H-benzimidazol-1-yl7-2-methylpropyl2$-4-piperidinyl7-1,3-dihydro-2H-benzimidazol-2-one as an oily residue, 6-chloro-1-^3-/'+- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl-7-propyl-1,3-dihydro-2H-benzimidazol-2-one hydrate, m.p. 179.6°C. dihydro-5, 6-dimethyl-2H-benzimidazol-2-one~ 2- propanolate-, m.p. 159°C. 2H-benzimidazol-2-one, m.p. 273°C, 1-^ 3-/ U- <( 2, 3-dihydro-'2-oxo-1H-benzimidazol-1-yl )-1-plperl-'dInyl7-propyl^-1, 3- dihydro-2H-benzimidazol-2-one, m.p. 225°C,

1;, 3-'dihydro-1-of-,/5-i('2:,3-dihydro-2~oxo-1H-benzimidazol-1-yl)-i-piperidinyl7propyl35-5-'( trif luormethyl))-2H-benzimidazol-2-one,

.'sm,.p.. 2'6'3','4'0fG;,

5-cl<br- 1_^'3-/2I-((.'2;, 3-dihydro-2-oxo-1H-benzimidazol-1-yl.')-1-piper"ri'dinyi7ProPyi3'-l 'j 3-rdibyd;ro-'2H-benzi'midazol-2-one, m.p.. •2'53-'25$'°''G:,

5-kIor^i^/t-- '3-/5;,::3-d-ibydro^<r>2-'okrso-?3-K'2-propenyl/)-IH-b'enz-i .mi'daz'ol'-i-y;17propyl -4-piperidinyl7-1,3-dihydro-2'H-benzimida-:zol-2--oil;, m.p. 153.4G'C:,

iL-^3-.£3','é-'dihydro-,4-'('2 , 3-'dihydro-'2-oxo-1H-benzimidazol-1-yl) - 1-'(2H ,)-pyridiyryl/propy1^-1., 3-dihydro-2H-benzimidazol-2-one,

'2'0'6.,'6°'C,

in

5-chloro^i^./I^.£3^/2, 3-dihydro-3-(1-methylethenyl)-2-oxo-1H-benz-imi'da<z>'<b>l --l-<y>l7<p>ro<p>.ylTj-4-<p>i<p>eridine<y>l7-1, 3-dihydro-2H-benzimida--x o

'z'6lw2--"on!, sm. pv 165.2 and

1-7^1H-b'enzine^ 3-dihydro-2H-bénzimidazbl-:2'-o'n, m.p. 157.1°C.

Example 9

A mixture of 5»3 parts of 1-(3-chloropropyl)-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one, 4.3 parts of 1,3-dihydro -1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.4 parts sodium carbonate and 200 parts 4-methyl-2-pentanone are stirred and refluxed 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 oily residue is purified by column chromatography on silica gel with a mixture of trichloromethane and methanol (90:10 parts by volume) as eluent. The pure fractions are collected and the eluent evaporated to give 6 parts (67$) of 1-(3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl-7-propyl)-3-1 , 3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one as an oily residue.

Example 10

In a similar manner as in example XXXI and with equivalent amounts of the relevant starting materials, the following compounds are prepared: 1-[3-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl7propyl]f-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one as an oily residue,

3-[3-(5-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl-7-propyl-1,3-dihydro-5-methyl-1 -(1-methylethenyl)-2H-benz-iraidazol-2-one as an oily residue,

1-[1-(1H-benzimidazol-1-yl)propyl]-4-piperidinyl-5-chloro-1,3-dihydro-2H-benzimidazol-2-one, m.p. 224°C and

5-Chloro-1-£1-(2-oxo-3(2H)-benzooxazolyl)propyl7-4-piperidinylT^-1, 3-dihydro-2H-benzimidazol-2-one, m.p. . 212.3°C

Example 11

A mixture of 5.4 parts 3-(3-bromopropyl)-2(3H)-benzothiazolone, 4.5 parts 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2- on, 5.3 parts sodium carbonate, 0.1 part potassium iodide and 200 parts 4-methyl-2-pentanone are stirred and refluxed for 3 hours with a water separator. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2-propanone. The product is filtered and dried to give 2.5 parts (31$) of 5-chloro-1,3-dihydro-1-£1-(3-(2-oxo-3(2H)-

benzothiazolyl)propyl (7-4-piperidinyl)-2H-benzimidazol-2-one,

sm.p. 184.1°C.

Example 12

Following the procedure described in 1 example XXXIII

one obtains 1-£1-/3-(1H-benzotriazol~1-yl)propyl7-4-piperidiny 1^-5- chloro-1,3-dihydro-2H-benzimidazol-2-one, m.p. 203.4°C, by reaction of 1-(3-bromopropyl)-1H-benzotriazole with 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2»one.

Example 13

A mixture of 5 parts of 1,3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one, 3.75 parts of 5-chloro-1,3-dihydro-1-(4- piperidinyl)~2H-benzimidazol-2-one, 2.65 parts of sodium carbonate and 22.5 parts of N,N-dimethylformamide are stirred at 70-80°C for 2 hours. The reaction mixture is cooled, poured onto water and the precipitated product is filtered off. It dissolves in trichloromethane. The solution is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone to give 3 parts (43$) of 5-chloro-1-£.1-(3-(1,3-dihydro-3-methyl-2-oxo-2H-benzimidazole- 1-yl)propyl7-4-piperidinyl3-1,3-dihydro-2H-benzimidazol-2-one, m.p. 166.5°C Example 14

A mixture of 7.6 parts of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one-methanesulfonate, 5.5 parts of 5-chloro-1,3-dihydro-1 -(4-piperidinyl)-2H-benzimidazol-2-one, 5 parts sodium carbonate and 63 parts N,N-dimethylformamide are stirred and heated in an oil bath at 50-60°C for 2 hours. The reaction mixture is poured into water. The precipitated product is filtered off, dried and purified by column chromatography on silica gel with a mixture of trichloromethane and 10% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized from a mixture of N,N-dimethylformamide and water. The product is again filtered off and dissolved in a mixture of 4-methyl-2-pentanone and a little N,N-dimethylformamide. The solution is filtered until it is clear and the filtrate is concentrated to an amount of approx. 10 parts by volume. The concentrate is triturated in methanol. The precipitate is filtered off and dried to give 1.27 parts of 5-chloro-1-33-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-i-piperidi- nyl7-propyl]3-1,3-dihydro-2H-benzimidazol-2-one, m.p. 229-236°C.

Example 15

A mixture of 7 parts 1-(3-chloropropyl)-5-fluoro-1,3-dihydro-3-(1-methyl)-2-phenylethenyl)-2H-benzimidazol-2-one, 5 parts 5-chloro- 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 4.25 parts sodium carbonate, 0.1 parts potassium iodide and 200 parts 4-methyl-2-pentanone are stirred at reflux overnight. The mixture is cooled to room temperature, water is added to the layers and separated. The organic phase is dried, filtered and evaporated. The evaporation residue is stirred and refluxed overnight with a solution of 55 parts hydrochloric acid solution 6N in 40 parts ethanol. The solvent is evaporated and the residue taken up in water. The mixture is made alkaline with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The evaporation residue is purified by column chromatography on silica gel with a mixture of trichloromethane and methanol as eluent (95 s 5 parts by volume). The pure fractions are collected and the eluent is evaporated. The evaporation residue is converted to the hydrochloride salt in 2-propanol. The salt is filtered off and dried to give 1.2 parts of 1-[3-(5-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl7propyl")-5 -fluoro-1,3-dihydro-2H-benzimidazol-2-one hydrochloride hydrate, mp 250°C.

Example 16

In the same way as described in example XXXVII, the following is prepared: 5-chloro-1-(1-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-butyl7-4-piperidinyl3T-1 ,3-dihydro-2H-benzimidazol-2-one hemihydrate, m.p. 258°C by reaction of 1-(4-chlorobutyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one with 5-chloro-1,3-dihydro-lT£4- piperidinyl)-2H-benzimidazol-2-one,

and

1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl-7-4-piperidinyl]-1,3-dihydro-3-(1-methylethyl)-2H- benzimidazol-2-one, m.p. 174.3°C, by reaction of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one with 1-(1-methylethyl)-3-( 4-piperidinyl)-2H-benzimidazol-2-one.

Example 17

A mixture of 6 parts of 1-β-[5-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl-7-propyl"3>-1,3-dihydro-5-methyl- 3-(1-Methylethenyl)-2H-benzimidazol-2-one, 12 parts hydrochloric acid solution, 30 parts water and 10 parts ethanol are first stirred for a while at 50°C and then for 1 hour at room temperature. The reaction mixture is evaporated and the residue crystallized from a mixture of 4-methyl-2-pentanone and 2-propanol. The product is filtered and dried to give 3.7 parts (40$) of l-£ 3-/ U-(2, 3-dihydro-2-oxo-lH -benzimidazol-1-yl)-1-piperidinyl-7-propyl-1,3-dihydro-5-methyl-2H-benzimidazol-2-one hydrochloride hydrate, mp 251.4°C.

Example 18

In a similar manner to example XXXIX, the following compounds are prepared from the corresponding (1-methylethenyl)" substituted analogues: 5-chloro-1--£1-(3-(2,3-dihydro-5-methyl-2-oxo -1H-benzimidazol-1-yl)propyl7-4-piperidinyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride hydrate, m.p. 213.3°C,

5-chloro-1-*£1-(2,3-dihydro-6-methyl-2-oxo-1H-benzimidazol-1-yl)propyl7-4-piperidinyl 3r-1,3-dihydro-2H- benzimidazol-2-one hemihydrate, m.p. 195.4°C, and

5-chloro-1-β1-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-2-A methylpropyl7-4-piperidinyl-1,3-dihydro-2H- benzimidazol-2-one, m.p. 2kk°C.

Example 19

A mixture of 38 parts carbon disulfide, 6 parts 1-/^l—^3-^N-(2-aminophenyl)amino7propyl^-4-piperidinyl7-5-chloro-1,3-dihydro-2H-benzimidazol-2-one and 32 parts ethanol are stirred and refluxed for 2k hours. The reaction mixture is evaporated and the residue is crystallized from ethanol. The product is filtered off and recrystallized from a mixture of N,N-dimethylformamide and water to give 3 parts (45.5%) of 5-chloro-1-£-1/3-(2,3-dihydro-2-thioxo-1H -benzimidazol-1-yl)-propyl7-4-piperidinyl3-1,3-dihydro-2H-benzimidazol-2-one, m.p. 266.6°C.

Example 2 0

A mixture of k parts l-/l-£3-/N-(2-amino-5-chlorophenyl)amino7-propyl^-4-piperidinyl7-1,3-dihydro-2H-benzimidazol-2-one, 6 parts concentrated hydrochloric acid solution and 30 parts formic acid are stirred at reflux overnight. The reaction mixture in-1 is evaporated and water is added to the residue. The mixture is made alkaline with dilute ammonium hydroxide solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated and the residue is crystallized from 4-methyl-2-pentanone, filtered and recrystallized from 2-propanol giving 1.1 parts (27$) l--£l_/3-(6-chloro-lH- benzimidazol-1-yl)propyl 7-4-piperidinyl 1,3-dihydro-2H-benzimidazol-2-one, m.p. 214.9°C.

Example 21

A mixture of 20 parts of 1-(3-4-[2-amino-4-chlorophenyl)amino7-1-piperidinyi3^propyl7-1,3-dihydro-2H-benzimidazol-2-one, 52 parts of carbon disulfide and 120 parts of ethanol are stirred at reflux for 24 hours. The reaction mixture is filtered after cooling and the filtrate is evaporated. The evaporation residue is crystallized from 2-propanol. The product is filtered off and recrystallized from ethanol which, after drying, gives 7.5 parts (34$) of 1-[3-(5-chloro-2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl) -1-piperidinyl/propyl['-], 3-dihydro-2H-benzimidazol-2-one, m.p. 254, 3°C.

Example 2 2

In a similar manner to that described in Example XLIII, 1-[3-(1-(2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl[1,3-dihyde] is prepared ro-2H-benzimidazol-2-one, m.p. 248.5°C by reacting 1-[3"-[4-(X2-aminophenyl)amino7-1-piperidinyl^propyl7-1,3-dihydro-2H-benzimidazol-2-one with carbon disulfide.

Example 2 3

A mixture of 2.21 parts of 1~£3-(1-(5-chloro-2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1-piperidinyl/propyl^-1,3" dihydro-2H-benzimidazol-2-one, 0.71 parts of iodomethane, 0.28 parts of sodium methanolate and 40 parts of methanol are stirred overnight at room temperature. The reaction mixture is evaporated. The evaporation residue is stirred with water and the product is extracted with tribr- ■ methane. The extract is dried, filtered and evaporated. The evaporation residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried to give 1.1 parts of l-/3-£4-/3-chloro-2-(methylthio)-lH-benzimidazole-l -yl7-1-piperidinyl3-propyl7-13-dihydro-2H-benzimidazol-2-one, mp 196.1°C.

Example 2 4

A mixture of 5 parts of 5-chloro-1-£1-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl7-4-piperidinyl-1,3-dihydro-2H -benzimidazol-2-one, 10 parts of acetic anhydride and 90 parts of methylbenzene are stirred at reflux overnight. The reaction mixture is cooled, water is added and the whole is made alkaline with dilute sodium carbonate solution. The layers are separated and the organic phase is dried, filtered and evaporated. The evaporation residue is crystallized from methylbenzene. The product is filtered off and recrystallized from methylbenzene which gives 4.5 parts of 3-acetyl-5-chloro-1-£1-(3-acetyl-2,3-dihydro-2-oxo-1H-benzimidazol-1- yl)-propyl7-4-piperidinyl N-1,3-dihydro-2H-benzimidazol-2-one, m.p. 185.3°C«

Example 2 5

To a stirred solution of 1 part of 5-chloro-1-[£1-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl7-4-piperidinyl-1 ,3-dihydro-2H-benzimidazol-2-one in 32 parts of ethanol is added a solution of 0.35 parts of (+)-2,3-dihydroxy-1,4-butanedioic acid in 8 parts of ethanol. After stirring, the product is allowed to crystallize. The crystals are filtered off and dried to give 1 part (+)-5-chloro-1-£1-(3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-propyl7-4-piperidiny 1*^-1,3-dihydro-2H-benzimidazol-2-one-2,3-dihydroxy-butanedioate-ethanolate, m.p. 153.5°C.

Example 2 6

A stirred solution of 1 part of 5-chloro-1-[1-(3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl7-4-piperidinyl 3''-1,3-dihydro- 2H-benzimidazol-2-one in 20 parts of ethanol is saturated with gaseous hydrogen chloride. This formed hydrochloride salt crystallizes with stirring. The crystals are filtered off and dried to give 0.6 parts (53$) of 5-chloro~l-£l-/ 3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl7-4-piperidinyl 3r-1,3-dihydro-2H-benzimidazol-2-one hydrochloride hydrate, m.p. 195 .7°C.

Example 2 7

A solution of 1 part of 5-chloro-1-j£1-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl7-4-piperidinyl 3r-1,3-dihydro-2H-benzimidazole -2-one in 40 parts ethanol is acidified with 2-propanol previously saturated with gaseous hydrogen chloride. During cooling, the hydrochloride salt formed is allowed to crystallize and 1 part (83$) of 5-chloro-1-£1-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) is obtained propyl 7-4-piperidinyl 3^-1,3-dihydro-2H-benzimidazol-2-one hydrochloride ethanolate, m.p. 213.7°C.

Example 2 8

10.2 parts of 5-chloro-1-β1-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl7-4-piperidinyl-1,3-dihydro- 2H-benzimidazol-2-one is converted to the (+)-2,3-dihydroxybutanedioate salt in 100 parts of water at reflux temperature. The solution treat-

read for 10 minutes with a mixture of 0.5 parts activated charcoal and 0.2 parts hyflo. The mixture is filtered over hyflo and the filtrate is cooled until an oily product is obtained. The precipitate hardens when heated. The whole thing is allowed to cool to room temperature and stirred for 3 hours at this temperature. The product is filtered off, washed with water and dried in vacuo for 18 hours at 60°C to give 10.24 parts (85.3$) of 5-chloro-l--£l-/3-(2,3-dihydro- 2-oxo-1H-benzimidazol-1-yl)propyl7-4-piperidinyl3-1,3-dihydro-2H-benzimidazol-2-one-hemi-/f?- (R*,R*|7 ( + )- 2,3-Dihydroxybutanedioate hydrate, mp 184.1°C, /α7= + 5.13° (c = 1$ ch3oh).

Example 2 9

A mixture of 6.7 parts of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one-methanesulfonate, 4.2 parts of 4-(4-chlorophenyl)-4-piperidinol , 3.2 parts sodium carbonate and 32 parts 4-methyl-2-pentanone are stirred and heated at 50-60°C for 1.5 hours. The reaction mixture is poured into ice-water. The precipitated product is filtered off and dissolved in trichloromethane. The solution is washed with water, dried, filtered and evaporated. The solid residue is purified by column chromatography on silica gel with a mixture of trichloromethane and 10% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is stirred in a small amount of trichloromethane. The product is filtered off and crystallized from 4-methyl-2-pentanone which gives 2 parts (24$) of 5-chloro-1-[3-([4-chlorophenyl)-4-hydroxy-1-piperidinyl]propyl-3T-1, 3-dihydro-2H-benzimidazol-2-one, m.p. 190.8°C.

Example -^ q

A mixture of 3.58 parts 1-(3-chloropropyl)-1,3-dihydro-5,6-dimethyl-2H-benzimidazol-2-one, 3.17 parts 4-(4-chlorophenyl)-4-piperidinol , 5.3 parts sodium carbonate, 0.2 parts potassium iodide and 160 parts 4-methyl-2-pentanone are stirred and refluxed for 24 hours with a water separator. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is converted to the hydrochloride salt in methanol and 2-propanol. The salt is filtered off and dried to give 1.7 parts of 1-[3-(4-chlorophenyl)-4-hydroxy-1-piperidinyl-7-propyl-1,3-dihydro-5,6-dimethyl-2H- benzimidazol-2-one hydrochloride, m.p. 260.8°C.

Example 31

A mixture of 2.3 parts 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 2.12 parts 4-(4-chlorophenyl)-4-piperidinol, 3.2 parts sodium carbonate , 0.1 parts of potassium iodide and 80 parts of 4-methyl-2-pentanone are stirred and refluxed for 36 hours. After cooling to room temperature, water is added and the layers are strained apart. The organic layer is dried, filtered and evaporated. The evaporation residue is purified by column chromatography on silica gel with a mixture of trichloromethane and 10% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from methylbenzene to give 1 part (26$) of l-£3-(4-chlorophenyl)-4-hydroxy-l-piperidinyl-7-propyl l^J-1,3-dihydro-2H-benzimidazole-2 -on, sm.p. 134.2°C.

Example 32

Following the same procedure as described in example LIII and using equivalent amounts of suitable starting materials, the following compounds are obtained: j-1,3-dihydro-2H-benzimidazol-2-one, mp 180.6°C, 1-/3~'C4-£'5-chloro-.3-(trifluoromethyl)phenyl7- 4-Hydroxy-1-piperidinyl-propyl7-1,3-dihydro-2H-benzimidazol-2-one, m.p. 18°.2°C,

1-[3-(4-chlorophenyl)-4-hydroxy-1-piperidinyl-7-propyl-3'-1,3-dihydro-3-(2-propenyl)-2H-benzimidazol-2-one, m.p. l4l.3°C,

1-4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl-7-butyl 3;'-1,3-dihydro-2H-benzimidazol-2-one, m.p. l60.6°C and

1-(1H-benzimidazol-1-yl)propyl7-4-(4-chlorophenyl)-4-piperidine-

, o

noi, sm.p. 160 C.

Example 3 3

A mixture of 5 parts 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 3.9 parts 4-(4-fluorophenyl)-4-piperidinol , 5.3 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone are stirred and refluxed for 48 hours in a water separator. The reaction mixture is cooled to room temperature, water is added and the whole is made alkaline with 15 parts of sodium hydroxide solution 60$, The layers are separated from each other and the organic phase is dried, filtered and evaporated. The residue is purified by column chromatography on silica gel with a mixture of trichloromethane and 10% methanol as eluent.

The pure fractions are collected and the eluent is evaporated. The oil residue is dissolved in 2-propanone. The solution is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride, and stirred under reflux for 15 minutes. The solvent is evaporated and the hydrochloride salt formed is dissolved in water. The free base is released in a known manner with dilute sodium hydroxide solution. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The evaporation residue is crystallized from methylbenzene, the product is filtered off and dried to give 2.5 parts of 1-£3-(4-fluorophenyl)-4-hydroxy-1-piperidinyl-7-propyl-1,3-dihydro-2H-benzimidazole-2 -on, sm.p. 135»4°C.

Analogous process for the preparation of therapeutically active 1-(benzazolylalkyl)piperidine derivatives of formula

and their pharmaceutically usable acid addition salts wherein:

R 1 and R 2 denote hydrogen, halogen, lower alkyl or trifluoro-

methyl,

B denotes a divalent group

-N=N- and -N=CH-, where L denotes hydrogen, lower alkyl, lower alkanoyl or lower alkenyl, and where said divalent groups are bound to the benzene nucleus with their heteroatom,

R 3 denotes hydrogen or methyl,

m and n denote numbers from 1 to 2 and

k 5 6

where R denotes hydrogen or lower alkyl, R and R denote hydrogen, halogen, lower alkyl or trifluoromethyl,

b) a group with formula

where R 7 and R 8 represent hydrogen, halogen, lower alkyl or trifluoromethyl, Y represents 0 or S, and the dashed line indicates that the double bond between the 3- and 4-C atom in the piperidine nucleus is optional, provided that when Y is equal to S there is a repulsive bond between the aforementioned 3- and 4-C atom in the piperidine nucleus and that M is then hydrogen,

c) a group with formula

9

where R denotes hydrogen, halogen, or trifluorome-

tyl and R denotes hydrogen or halogen, characterized in that one

a) converts a compound with formula

S

1"

where B has the same meaning as B except -NH-C-, and X denotes a suitable reactive ester function derived from the corresponding alcohol,

with a compound of formula

in a suitable organic solvent, for the preparation of a compound of formula

or

b) removes the protecting group P in a known manner from a compound of formula

for the preparation of a compound of formula

or

cj ring-closes a compound with formula

by means of a suitable ring-closing agent in a known manner, for the preparation of a compound of formula

0 S

2

where B denotes -NH-C-, -NH-C- or -N=CH- or

d) ring-closes a compound of formula

in a known manner by means of suitable ring-closing agents, for the preparation of a compound of formula

or

e) and in compounds where L is hydrogen introduces L equal to lower alkyl or lower alkanoyl, and

if desired, prepare pharmaceutically acceptable acid addition salts of the products obtained in processes a to e.

Claims (3)

1. Method for stabilizing the roughened surface of textiles made of fibers of synthetic linear polymers of acrylonitrile, characterized in that the roughened textile is treated with an aqueous solution of ethylene carbonate at a concentration of 0.05-2.0%, which also contains a silicone resin emulsified after which the ethylene carbonate is concentrated and dried by heating, whereby a permanent bond is formed between the fibers at their crossing points. 2. Method according to claim 1, characterized in that the textile is heated for 5 to 60 minutes at 115-150°C. 3. Method according to claims 1 and 2, characterized in that the aqueous solution of ethylene carbonate contains a silicone resin emulsion in quantities of 0.2-5 percent.