CS202550B2 - Method of preparing novel derivatives of 1-/benzazolylalkyl/piperidine - Google Patents

Abstract

1-(Benzazolylalkyl)piperidine derivatives of formula I <IMAGE> and their salts are prepared by subjecting an amine of formula <IMAGE> to N-alkylation to introduce the corresponding substituted alkyl radical. In the compounds of formula I, the substituents have the meanings given in Patent Claim 1. These compounds and their salts have a spasmolytic action and they are in particular used in agents to prevent vomiting.

Description

The invention relates to a group of 1- (benzazolylalkyl) piperidine derivatives which are useful as anti-emetic agents.

A variety of benzazolylalkyl and indolylalkyl substituted piperidine derivatives and a variety of aminoalkyl substituted benzazoles are known in the literature, some of which have a pharmacological, for example, antidepressant, pancreatic, antihistamine or entispasmogenic effect.

Among other differences, the compounds of the present invention differ from these known compounds either by the benzazole and / or substituted piperidine moiety *

The following references can be made from a number of the above-mentioned literature:

Int. Pharmacopsychiat. 1968 (1), pp. 214, ₍ CA, 64, 2093b (1966),

22, 111466 (1970). C.A., 81, 120632b (1970).

Fr. Pat. No. 2,042,321 (Derw. Fr. Week S 16, Pharm. p. 12), and Belg. U.S. Pat. No. 753 472.

The present invention provides a process for the preparation of novel 1- (benzazolylalkyl) piperidine derivatives of formula (I)

and their pharmaceutically acceptable salts. suitable salts, where,

R 1 and R 2 are each independently hydrogen, halogen, methyl or trifluoromethyl; 0 N O0 n Mt II »

B is selected from the group consisting of divalent radicals -N. (L) -C-, -NH-C-, -S-C-, -O-C-,

-N = N- and N'CH-, wherein L is hydrogen, methyl, acetyl, 2-propenyl and 1-meethlethenyl, and these divalent radicals are attached to the benzene ring by a heteroaoom; 1, man '' are all numbers 1 or 2 and.

the rest is selected from the group "Including:".

(a) the rest of the face

^kd e ^R4 is hydrogen and · metltyl Neto and ^R6 are independently hydrogen ^{It runs} with water ^ u, ^{H allogenic,} mmttyl Neto ого ^^^ ^^! »

b

(B) β

where R 'and R ° are each independently hydrogen, hydrogen or halogen;

Ϊ e ttomn lyslíu or аЮш sulfur,

Boiler-water, alkyl of up to 4 amino atoms, acetyl and the dashed line indicate that the double bond between carbon atoms 3 and 4 of the piperidine nucleus is optional, and when Ϊ is a sulfur atom it is between carbon atoms 3 and 4 of the piperidine nucleus a single bond and M is a hydrogen atom,

c) a residue of formula C

(C)

Wherein R and R are each independently hydrogen, halogen, methyl or trifluoromethyl, and alkyl has 1 to 5 carbon atoms and

d) a residue of formula D

(D)

Q10 * wherein R is hydrogen, halogen or trifluoromethyl and R is hydrogen or halogen which is characterized by reacting a compound of formula

(II) wherein B ¹ has the same meaning as defined above, except В -NH-C (S) -, X is an appropriate reactive ester function derived from the corresponding alcohol of Rp and Rg »^ 3» ^{m and n} are as defined above, with a compound of wherein A is as defined above, in an organic solvent, and optionally pharmaceutically acceptable salts are prepared.

(III)

4 The condensation reaction ae β is preferably carried out in a suitable organic solvent such as lower alkanols such as methanol, ethanol, propanol, butanol and the like, alcohol, aromatic hydrocarbon such as benzene, methylbenzene, dimethylbenzene and the like, ketone such as 4-methyl-2 -pentanomju ,. an ether such as 1,4-dioxane, ΤΠ'-oxybisethane and the like, Ν, Ν-dimethylformamide, nitrobenzene and the like. By adding a suitable base such as an alkali metal or alkaline earth metal carbonate or acid carbonate, the acid liberating during the reaction . A small amount of the appropriate metal iodide, for example sodium iodide or potassium iodide, may be added to initiate the reaction, especially when chloride is used as the reactive ester. A somewhat elevated temperature is suitable for increasing the reaction rate and preferably at the point boiling the reaction mixture. In this and the following procedures, the reaction product is separated from the reaction medium and optionally further purified using conventional methods.

The starting materials used in the process of the present invention can be obtained by the processes described above. Reactive esters of formula II, which may be represented by formula IIIa

¹ 2 2 wherein R a, R, m, n, B and X are as defined above, may be prepared as follows:

An appropriately substituted 2-chloronitrobenzene of formula VIII is reacted with a suitable aminoalkanol (XX) in a suitable reaction-inert solvent such as a lower alkanol such as ethanol, 2-propanol, butanol and the like to form ['(2-nitrophenyl) The aminoJ alkanols of formula X in which the nitro group is then reduced to the amino group, for example by catalytic hydrogenation, using Raney nickel as a catalyst. The thus obtained f (2-aminophenyl) amino] alkanol of formula XX is then reacted with the appropriate cyclizing agent described above to prepare compounds of formula Ic from compounds V _} and the alcohol of formula XII thus obtained is converted to the desired inactive ester (IIIa). in a conventional manner.

Halides are preferably prepared by reacting compounds of formula XII with an appropriate halogenating agent, such as sulfinyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus tribromide, phosphoryl chloride and the like. If the reactive ester is iodide, it is preferably derived from the corresponding chloride or bromide . Other reactive esters, such as methanesulfonates and 4-methylbenzenesulfonates, are obtained by reacting the alcohol with the appropriate eulfonyl halide, such as methanesulfonyl chloride and the like.

4-Methylbenzenesulfonyl chloride.

The foregoing reactions are illustrated in the following scheme:

+ H ₂ H- (CH ₂ ) _and -CH- (CH ₂ ) _n -OH ---------->

(IX).

(VIII)

202550..

R ³ ° ² ^, ^{NH— ( CH} 2) m - C ^H - ( ^c H ₂ ) _{n -} OH Hg / RaNi

R ¹ R ² (X) 'v

cyclization -------->

(XII)

Formation of Reaction --------- ----- (Ha) -active ester.

The intermediates of formula II represented by formula IIb

(lib) v 1 oo where R, R, ^RJ , m, n and X are as defined above and В is a group of the formula -SC (O) -, -0-0 (0) -, N = N-, - N = CH-, or -N (L ¹ ) -O (O) -, wherein L ¹ is lower alkyl, lower alkenyl or lower alkylcarbonyl can also be prepared by introducing a reactive side chain into the starting material of formula XIII. *

(XIII) in a manner known per se. For example, the hydroxyalkyl chain may first be introduced by N-alkylation. the compound of formula XIII with a suitable haloalkanol of formula XIV by a conventional N-alkylation procedure to give an alcohol of formula XV, wherein the hydroxyl group is then converted to a reactive group as described above. Tetrahydro-2H-pyran-2-yl ether derivatives may also be used in place of haloalkanol (XIV), whereby. the corresponding ether derivative (XV) is obtained and the ether functional group is opened by acid hydrolysis, for example by stirring and heating the ether in dilute hydrochloric acid.

If the reactive ester (II-b) is a halide (II-b-1), it can alternatively be prepared by reacting a compound of formula - XIII with an equivalent of the corresponding dihaloalkane (XVI) in the presence of an appropriate strong base, such as sodium methanodide or according to Maakksza, using aqueous alkaline and quaternary ammonium cadmium such as N, N, N-Streptyllylbenzene-ethanamine chloride to give the desired meel product. (II-b-1). .

The above process may be illustrated by the following scheme:

^r3 (XIII) + hydrogen- (CH ₂ ) _m pCH- (CH ₂ ) _n pOH М-писг ^ сс (XIV) '

R ³

-CH- (CH _{2) n} -OH formation of reactive - ¹ ------------> (II-b) ester (XV)

B ³ (XIII) + Hl- (CH ₂ ) _IB pCH- (CH ₂ ) _n phalogen

R ^{3 (} CH 2 ^{) m} - CH - (CH 2) ^{n -} halogen

R ^ R ² bases

----------: ------- _> II-b-1

Meelproducts of formula-

(II-c) wherein B, R-, B-, m, n, and X have the meanings given above, can be prepared by introducing a reactive ester side chain into the starting material of formula X7II

(XVII) wherein P is a suitable protecting group as defined above and after elimination of the protecting group in the compound of formula XIX thus obtained by a conventional method described above. The introduction of the reactive side chain can be carried out in a similar manner as described above for introducing the side chain into the starting materials of formula XIII. More precisely, the hydroxyalkyl chain is first introduced, whereupon the h-hydroxyl group of the thus obtained intermediate (XIII) is converted to a reactive ester group to form a compound of formula XIX or if the reactive ester is a halide · (XIXa), (XII) with the corresponding dihaloalkane. If the protecting group P is a group that undergoes alkaline hydrolysis, such as lower alkyloxycarbonyl, methylsulfonyl or 4-methylbenzenesulfonyl, then the N-alkylation reaction for introducing the hydroxyalkyl or haloalkyl chain must be carried out under non-hydrolytic conditions using, for example, an appropriate metal base, such as sodium hydride or sodium methanolate, in an appropriate aprotic organic solvent, such as N, N-dimethylformamide, N, N-dimethylacetamide or phosphoric acid.

Pre-reaction reactions can be seen in the following scheme:

(XVII) + (XIV) ^ alkylation + (XVI) v '

(XIII)

creation of reactive

(II-c-1) ester

(XIX) elimination of P (II-c)

Intermediates of formula II-d

(H-d)

Wherein R, R, R 6 and X are as defined above and L is lower alkyl. or lower alkenyl, wherein the lower alkenyl has a double bond at the beta, gema or delta positions can also be prepared as follows:

The intermediate of formula II-c, wherein m and n are 1 (II-c-2), is reacted with sodium metal in absolute ethanol to form a cyclic ether of formula. XX. This compound is then reacted with the corresponding reactive ester L X (XXI), wherein L and X have the meaning given above, for example by heating the reaction. in 2-propanone, to give the desired intermediate (H-d).

II-c-2

. - (XXI) II-d

Compounds of formula IV used as intermediates in the preparation of compounds of formula I-b can generally be prepared by condensation of an intermediate of formula XIX with an associated intermediate of formula III under the conditions described above for the preparation of compounds (Ia) from compounds II and III.

(XIX) + (III) -------------- (IV)

and which are referred to as IV-b _; can also be prepared by condensation of the corresponding reactive ester of formula (XIX) with the associated N- (2-nitrophexyryl) -4-piederdiaamine of formula XXH, followed by reduction of the nitro group of the compound of formula XXII thus formed, by conventional methods used to reduce the nitro group to amino; is, for example, by reacting the nitro compound with a 202550 moiety at birth or by catalytic hydrogenation in the presence of a suitable catalyst such as Raney Nickel ¹ and cyclizing the resulting benzenediamine (XXIV) with the cyclizing agent described above.

The foregoing reactions may be illustrated by the following scheme:

. (XXIII) to the amino group of the nitro group reduction

(XXIV) cyclization • in (IV-b)

The starting materials of formula XXII can be prepared according to the methods of U.S. Pat.

9Ю 930.

The intermediates of formula (V) are obtained by condensation of the corresponding reactive esters of formula XXV with the corresponding piperidine derivative of formula III and then reduction of the nitro group in the thus obtained intermediate (XXVI) to the amino group according to conventional procedures for standard nitro to amino group procedures.

AND

202550 '10

reduction of the nitro group ------------: ------------------> (V) to the amino group (XXVI)

The reactive esters of formula XXV used as starting materials are readily prepared from the alcohol of formula X by converting the hydroxyl functionality to a reactive ester group conventionally known in the art. - <· - ;; ·. <. .... ...... .....

Intermediates of formula VI are generally prepared by condensation of the corresponding reactive esters of formula II with the appropriate N- (2-nitrophenyl) -4-piperidinamine of formula XXII and subsequent reduction of the nitro group to the amino group to give a compound of formula XXVII _; a procedure commonly used to reduce a nitro group to an amino group as described above.

• č

It should be noted that when the reduction of the nitro group to the amino group is carried out by catalytic hydrogenation using palladium on carbon catalyst, dehalogenation may occur in the presence of a halogen atom bound to the aromatic ring.

(II) + (XXII)

(XXVII) nitro reduction

--------: ---—--> (VI) to an amino group

Similarly, intermediates of formula (VII) may be prepared by condensation of a reactive ester of formula (XXV) and a piperidine derivative of formula (XXII) and then reduction of both nitrogroups у thus obtained with a compound of formula (XXVIII) by the procedures described above.

J 202550 (XXV)

reduction of the nitro group -----------------: --------------> to the amino group (VII)

Starting materials of formula III represented by formulas III-a, ΙΙΙ-b and IXI-c

(II-a)

C)

(III-c) and methods for their preparation are described in the following patents:

a) US Pat. No 3 238'216,

b) US Pat. No. 3,161,645, Belgian Patent No. 830,403, U.S. Pat. c) US Pat. No. 3,518,276 a.

US Pat. No. 3,575,990.

Starting materials of formula III of formulas III-d and III-e

(Il-e)

202550 -. '’. - '12' can generally be prepared from the corresponding.ch. N- (2-aminophenyl) -4-piperidinamine of formula XXIX:

(XXIX). .

The starting materials (ΙΙΙ-d) are preferably prepared by cyclizing compound XXIX with a suitable cyclizing agent, for example carbon disulfide, followed by cleavage of the lower alkoxytrbonyl group in the compound of formula XXX thus obtained by alkaline hydrolysis. ,

The starting materials (III-e) can be prepared by S-alkylation of the compound of formula XX as described above. above, and then eliminating the lower carbocarbonyl group in the resulting compound of formula XXXI.

N- (2-Amino-enyl) -4-piperidines of the formula HX 4, many of which are nifo, can be prepared according to the methods of U.S. Pat. No. 3,910,930 and the Belgian patent. No. 830 403.

¹ Previous ^ c! . the procedures are illustrated in the following diagram:

(R XIX) (lower alkyl) -O-C-N

cyclization v

OH '.

---> dIid

AND

OH '(Ille) (XXXI). 13 ‘202550

The last starting materials in all of the foregoing preparations are generally known or can be prepared in a manner known per se for the preparation of similar compounds. *

For example, preferred starting materials of formula XII, wherein P is an appropriately substituted eehenyl group (XII-a), of which most are known compounds, can be prepared by a known method described in J. Chem. Soc. 1960, pp. 308 and 314.

More specifically, these compounds are prepared by reacting the corresponding ester of formula НИ, where R and R 'are as defined above with the corresponding benzenediamine of formula ШИ. These reactions are preferably carried out by stirring and heating to boiling the reactants in a suitable inert organic solvent under azeotropic distillation water. Suitable inert organic solvents for this purpose are aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene and the like.

(XXXII) ₁₁ c

R-CH-C-O-C (thio)

C = 0

AND··

. (III-a)

The intermediates of formulas I, II and III are novel and constitute a further feature of the invention as intermediates for preparing the desired compounds of formula I.

The compounds of the invention can be converted to therapeutically acceptable acid salts by reaction with an appropriate acid, for example an inorganic acid such as hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid and the like, sulfuric acid, nitric acid, phosphoric acid and the like. or an organic acid such as, for example, acetic acid, propionic acid, haloacrylic acid, 2-cypropioic acid, pyruvic acid, malonic acid, succinic acid, mmleic acid, fumaric acid, acid malic acid, tartaric acid, S-hydroxy ^ -C ^, 3-propane tricarboxylic acid, benzoic acid, S-phenyl-S-propenoic acid, alpha-! ^r YDL oxybenzenoctová acid, methanesulfonic acid, ethanesulfonic acid, beizeisulfoiová acid, 4-metthrlbenzzniuUfonová acid, cyclohexanesulfic acid, S-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and the like. oli can be converted to the free base by reaction with alkali L.

Compounds of formula I and their therapeutically active salts. Acids have a potent anti-vomiting effect, as demonstrated by their ability to prevent vomiting in dogs induced by moofin.

The method of testing was described in P. A. J. Jansen and C. J. E. Niemegeers in cForsch. (Drug Ree.), J., 765-767 (1959).

The compounds listed below were administered subcutaneously in CM at various doses, and after one hour a standard dose of 0.31 apomoofin was administered subcutaneously.

In the tables below, the values of a number of compounds are shown. Εϋ ^ θ values indicate the dose that protects 50% of the animals from vomiting. .

It is to be understood that the compounds listed in the table do not in any way constitute the present invention, but merely are examples of anti-emesis activity of compounds having the scope of Formula I.

Table I

. . L R ¹ : R ⁴ R ⁵ mg ^ kg s.c. H H H H 0.03 H 5-C1. H H 0.05  H _5-CH3 H H. 0.06 CH ₃ H . H H · 0.08 CH ₂ = CH-CH ₂ H H H 0.25 H 'H H, . 4-F 0.04 H 5-C1 и ' 4-F 0.015 H H H 3-CF ₃ 0,025 . H H СН3 H .0,015

TabixLka II

L R ¹ R ² r'3 O R? salts and solvates ^ED 50 mg / kg H H H H Ό H - 0.02 • H 5-C1 H H Ό H - ’ 0.10 H 5-CH3 6-CH3 H Ό H C ^-CHOH-C ^ - - 0.45 H H H СН3 O 5-C1 0.06 H H H H Ό 5-C1 -, 0.01 H 5-C1 H H Ό 5-C1 '- . 0.12 СН3 H H H O 5-C1 -. 0.16 ch ₂ = ch-ch ₂ H H H O 5-C1 '- 0.12 H · H ‘H H O H - ’ 0.04

EDjO

L r1 R ² r3 Ό r? salts and solvates mg / kg s.c. H ' 5-F H H 5-C1 HCl h ₂ 0 0.004 H _5-CH3 H H O 5-C1 HCl h ₂ 0 0.12 C (CH ₃ ) = CH ₂ H H. H O 5-C1. '- 0.20 H _5-CH3 H H Ό H HCl HgO 0.20

Table III

EL

mg / kg s.c.

H, 4-C1H

CH ₂ = CH-CH ₂ 4-C 1 H

H. 4-C13-CF

0.06

0.50

0.015

Table IV Compound

ED50 mg / kg · s.c.

O

0.25

0.001

0.03

ED ₅₀ mg / kg sc.

> 025.50.

Table IV - continuation of compound s

Cl

0.004

0.06

O

0,025

0.004

In view of the anti-vomiting effect employed, the compounds of the invention may be formulated into various pharmaceutical forms suitable for administration. For the preparation of the pharmaceutical compositions of the invention, an effective amount of a particular compound in the form of a base or salt with an anti-vomiting acid is intimately mixed with the pharmaceutical carrier, which carrier may vary depending on the form. of the preparation required for application. These pharmaceutical compositions are preferably in unit dosage form suitable for oral administration, rectal administration or injection. For example. any conventional pharmaceutical medium, such as, for example, water, glycols, oils, alcohols, and the like, may be used in the preparation of the compositions in oral dosage form; 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 the preparation of powders, pills, of capsules and pills. Because of their ease of administration, tablets and capsules form the most advantageous unit dosage form in which solid pharmaceutical carriers are employed. For parenteral compositions, the carrier will usually comprise sterile water, at least as the main ingredient, although other ingredients may also be used, for example, formulations may be prepared wherein the carrier is saline, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared using liquid carriers, suspending agents and the like. Salts of acids of formula I due to their increased solubility in water over free bases are of course more suitable for the preparation of aqueous compositions.

It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration of uniform doses. Dosage unit form as used in the specification and in the present invention means a dose suitable for single doses, each containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including tablets for division or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions and the like.

The amount of active ingredient per dosage unit is from about 0.25 to about 100 mg, and preferably from 1 to 50 mg.

The following preparations are examples of pharmaceutical compositions according to the invention used for vomiting in unit dosage forms suitable for systemic administration to animals and humans.

Oral drops:

50 liters of a solution of oral drops containing 10 mg of 5-chloro-1- {3- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -4 is prepared from the following ingredients. -piperidinyl-1,3-dihydro-2H-benzimidazol-2-one as active ingredient per ml.

active ingredient 500 g 2-hydroxypropanoic acid 0.5 liter saccharin sodium salt 1,750 g cocoa flavor 2.5 liter cleaned water 2.5 liter polyethylene glycol Fill up to 50.0 liters

The active ingredient is dissolved in 2-hydroxypropionic acid and 1.5 liters of polyefhylene glycol at 60-80 ° C. After cooling to 30-40 ° C, 35 liters of polyethylene glycols are added and mixed well. A solution of saccharin sodium in 2.5 liters of purified water is then added and cocoa flavor and polyethylene glycol are added to the desired volume with stirring. The resulting solution is filled into suitable containers.

Injectable solution »

20 liters of parenteral solution containing 2 mg are prepared from the following ingredients

5-chloro-1- {1- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -propyl] -4-piperidinyl | -1,3-dihydro-. -2H-benzimidazol-2-one active ingredient per ml.

active ingredient 40 g .tartaric acid 20 g methyl 4-hydroxybenzoate 36 g propyl 4-hydroxybenzoate 4 g water for injections up to 20 liters

Methyl and propyl 4-hydroxybenzoates are dissolved in about 10 liters of boiling water for injection. After cooling to about 50 ° C, tartaric acid and then the active ingredient are added with stirring. Solution

202550 'is cooled to room temperature. and filled into the desired volume with νοάομ for injection. The solution was filtered by filtration (U.S.P. XII, ttr. 811) and filled into sterile vials.

Oral solution: · ‘*

The following formulation provides 20 liters of an oral solution 5 mg obsaahUícího Chho-5-one - £ - ^ 3- (2, 3-d ^ih ydro-2-sxos i ^ b ^ NZIMA idazz-1 - ^yl) - ^p ro ^p -4- yl ^PIP eridinylj - ^1, 3-dihydro-2H-2-benzimidszol CNU as an active ingredient per teaspoonful (5 ml).

active ingredient 20 -g tartaric acid 10 g sachaain 'sodium salt 40 g 1,2,3-propratriol 12 liters torbitrl 70% solution 3 liters mm ethyl 4-hydroxyethrate  9 g propyl 4-hydroxyetherate  1 g mmainová - essence ' 2 ml gooseberry essence 2 ml cleaned water up to 20 liters

Methyl 1- and propyl 4-hydroxybenzoates are dissolved in 4 L of boiling purified water. In 3 l of this solution, the tartaric acid is first dissolved and then the active ingredient. The last solution is mixed with the remainder of the pre-drying solution and a solution of 1,2,3-proprantririum and sorbitol is added. The saccharin sodium is dissolved in 0.5 L of water and raspberry and gooseberry essence are added. The latter solution is added to the previous solution, treated with water do'požadovaného volume and the resultant solution was ^p CONSTANTS into suitable vials.

Tablets. Coated with fiheemj.

000. Tablets, each dispensed. Mon 10 mg of the active ingredient 5-chhor-1- {J-C3- ⁽² З ^ ^ ДОг -юо- ^1H - ENN ^{i e} I ^m ddaz ^{about 1} l - ^yl) - rr ^p y ^{p y} i] -4 - ^p and ^{p-piperidine yl -} 3 ^"d H ^y dro-2H-imidazol ^ -one ienz ready! from the following components:

Tablet cores:. .

active ingredient 100 g Lactose 570 g Starch 200 g pólyvinylpyrrriidon (Kollidon K90), 10 g mikkokkyysa ^y ical cellulose (Avicel) 100 g of sodium dooeeyyluufát 5 g hydrogenated vegetable oil (Sterotex) 15 g

Coating:

meethycellulose (Methocel '60 HQ). - 10 g ethylcellulose (Ethoce ^y 22 cps) 5 g, 2,3-propyralnerirl 2.5 ml polyethylene glycol 6 00010 g concentrated dye suspension .30 ml (Opaspray K-1-21.09).

polyvinylpyrrolidine (Povidme) 5 magnesium octadecanoate 2.5 g

20255Ó

To prepare tablet cores:

The mixture of active ingredient, lactose and starch is intimately mixed and then moistened with sodium dodecyl sulfate solution and polyvinylpyrrolidone in about 200 ml of water is added. The wet powder mixture is sieved, dried and sieved again. Microcrystalline cellulose, and hydrogenated edible oil are then added. The mixture is intimately mixed and compressed into tablets.

Coating:

A solution of ethylcellulose in 150 ml of dichloromethane is added to a solution of methylcellulose in 75 ml of denatured ethanol. 7 ml of dichloromethane and 1,2,3-propanediol are then added. The polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The latter solution is added to the first and then magnesium octadecanoate, polyvinylpyrrolidone, dye suspension concentrate are added and the mixture is homogenized.

The tablet cores are coated with the thus prepared mixture in a coating apparatus.

Suppositories;

100 suppositories each containing 30 mg of 5-chloro-1- {1- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -propyl] -4-piperidinyl-1, 3-Dihydro-2H-benzimidazol-2-one as the active ingredient is prepared from the following ingredients:

active ingredient / 3 ε tartaric acid 3 ε polyethylene glycol 400 25 ml surface active (Sleep) 12 G triglycerides. (Wit < 555) up to 300 G

The active ingredient is dissolved in a solution of tartaric acid in polyethylene glycol 400. The surface active ingredient and triglycerides are melted together. The latter mixture is well mixed with the preceding solution. The mixture thus obtained is poured into molds at 37-38 ° C and suppositories formed.

In view of the anti-emesis effect of the compounds of the invention, the invention relates to a method of inhibiting emesis in warm-blooded animals by systemically administering an effective amount of the compounds of formula I and their pharmaceutically acceptable salts in admixture with a pharmaceutical carrier.

The following examples illustrate the invention in more detail without restricting it in any way. Unless otherwise stated, all parts are parts by weight.

Prikladl v.

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 boiling. Stirring is continued overnight. The reaction mixture was cooled and evaporated. Water was added to the residue, and the mixture was acidified with a hydrochloric acid solution. The product was extracted with methylbenzene. The extract was dried, filtered and evaporated. The solid was recrystallized from petroleum ether. The product was filtered off, dried to give 141 parts (100%) of 3- (2-nitro-4- (trifluoromethyl) phenyl) amino] -1-propanol.

Example2

Using the procedure of Example 1 and using equivalent amounts of the respective starting materials, the following were prepared:

3 - [(4-Isopropyl-2-nitrophenyl) amino] -1-propanolol in the form. evaporator,

3 - [(4,54dichllr) -2-nitlofnyrl) Minle]) 1) .p _Γ lpanol, mp 97 ° C, .and

3 - [(2-chloro-6-nitrfferl) amino] -1-proianll as a residue.

EXAMPLE 3 A mixture of 70 parts of 3- (4-methylphenyl) amino-1-oxo-1-ol and 400 parts of methanol is hydrogenated under normal pressure at room temperature with 10 parts of 10% palladium on H 2. · After consumption of the calculated amount of hydrogen. katalyzátor.odfiltruje the filtrate is obtained odpaří.a · '54 parts (91 ·%) 3 3 ^2-aminοo4 miehhlfenyl) aminοl -1-propanol as a residue.

Example 4. , ^S mes ^{141 parts} 3-j [2-nl.Ιπ- ^ Ιγ ^^ - ^ ζΙ ¹¹ ^ - ^! ^1] ^ -aminol- proparnom ^d and ¹²⁰⁰ d ^profiles of methanol was hydrogenated at normal pressure and at room temperature with 15 parts of mstnooti re-Ίny-nikll.

. After the calculated amount of hydrogen had been consumed, the catalyst was filtered off and the filtrate was evaporated. Evaporate. crystallized from 2,2-O -pan to give 110 parts (100%) of 3- (E22) amni-4- (trifluoromethyl) phenyl] amino-1-propanol.

Example 5

Following the procedure of Example 4 and using the equivalents of the respective starting materials, the following were prepared:

3 - [(2-amino-, 5-dichlorophenyl) amino] -1-propanol, m.p. = 1185 ° C, 3 - [(2-amino-6-chlorophenyl) amino] -1-iraniline as a residue,

3 - [(2-Aminol-4-chlorophenyl) amino-14-propyl] as an oily residue.

Example 6 '

To a stirred and cooled solution of 54 parts of 3- (2-amino-4-methylphenyl) amino-14-propyl in 30 parts of a 10% hydrochloric acid solution and 200 parts of water is added dropwise a solution of 28 parts of potassium cyanate in 50 parts of water at below 10 ° C. After completion of the stirring, stirring was continued for 1 hour at room temperature and then for 24 hours at the boiling point. After cooling to room temperature, the product was extracted with HCl. The extract was washed with 5% hydrochloric acid solution, filtered and then evaporated. The residue was recrystallized from 4-methyl-24-pentanone to give 19.5 parts (31%) of 1,3-dilyl-1,4- (polyhydroxyproyl) -5-ethyl-22H-bromo-4-azazol-4-one, m.p. 114.1 ° C. . .

P Pila d * 7 ·

Following the procedure of Example 6 and using the equivalent starting materials, the following were prepared:

3-Hhydro-1 - (l-hydroxypropyl) -5- (triflюriethyl) -2H-bbnnimiddzzO-2-LN, 5 б4 ^d ic ^l-lor first, 4dd dl-- ^l h ^d) - (4 liters ^{ydr loxyρropyl)} 22H- rοz ^{b i} i ^d azol- ² -lο tt ^ 4.7 ^o C, e-chloro-! 3- ^d Ily ro ^d-34 (3-hydrlxyproiyl) -2H-benziIni azoO ^d-2-one, · and 5-chloro-1,3- ^d llyddro-1-t-lУd ^¢ rroxlirlill) -2H-beοziii ^{d to} ₍ oO ~ 2-o, mp 1.48.8 ° C).

Example. * 8 · ’

To 18.5 parts míchanému.roztoku 1,34dilydrl 1- (з-ly rlxyproiyl ^d) -54methyl-'2H-brnzimida-. of z424-one and 325 parts of dichloromethane are added 11.9 parts of Ν, Ν4-diethylelthonium. . Subsequently, 11.5 parts of mercuryl chloride were slowly added dropwise. After completion, the reaction mixture was stirred for one hour at the boiling point. After cooling, the mixture was washed with water, dried, filtered and filtered. The solid is crystallized from. 4-meet: h-24-pentanoic acid to give 15 parts (58%) of 1,3-dihldrl-14 (α-ldr144-propyl) 45-methyl-2H-bromoidazol-4-one methanesulfonate, mp 125 ° C. .

21.

Example 9, _v

Following the procedure of Example 8 and using equivalent possibilities of the appropriate starting materials, the following were prepared:

3- (5,6-Dichloro-2,3-dihydro-2-oxo-1H-benzimiddaol-1-yl) -propyl methanesulfonate as an oily residue,

3- (7- [4- (2,3-dihydrol-2-yl) -1H-benzimidazol-1-yl) -propyl] -3- (5-chloro-2,3-diidro-2-oxo-1H-benzimidazole) O- 1-yl) -propyl methylsulfonate, mp 1.140 ° C.

For example, o. ,.

May 30 parts of 1 H-benzoimidazole, 49 parts of 2- (4-chlorobuthoxy) -teraadydlo-2H-pyran, 21 parts of potassium hydroxide and 200 parts of ethanol are stirred and heated to boiling overnight. The reaction mixture is cooled to room temperature, filtered and the filtrate is evaporated. The residue is stirred in water and extracted with dilute hydrochloric acid. The mixture was stirred and heated in a water bath for 30 minutes. After cooling to room temperature, the product was extracted with toluene. The aqueous phase was separated, made alkaline with ammonium hydroxide. . The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. 50 parts of 1H-benzimidazol-1-butanol are obtained in the form of an oily residue.

p Pik ia ali.

To a stirred network of 23 parts of 1,3-dihydro-1- (3-hydroxypropyl) -5- (trifluoromethyl-22H-benzoimidol-2-one) in 150 parts of trichloromethyl is added dropwise 32 parts of uulfioyl citride. At the end of the dropwise addition, the reaction mixture was heated to reflux and stirred for one hour, and after cooling, the reaction mixture was evaporated and the residue was crystallized by 2,2 ' -othybispropane to give 14 parts (56 parts). %) of 1- (3-Οί1ογργο [^ 1-L13-diih ddro5- ^r (trifluoromethyl) -2H-benoimidtool-2-lou..

. Example 12 * ·

- Using the procedure of Example 11 and using equivalent amounts. The following chlorides are prepared as the starting material of the corresponding hydrocompounds:

5-chloro-1- (3-chloropropyl) -1,3-iodo-2H-benzimidazol-2-one,

6-Cillr-1- (3-chloro-propyl-1, Zididyr-22H-benoimidtoll-2-oo, mp 122 ° C, and

1- (4-Cyclobutyl-1H-beimidimidole) as an oil residue.

Example 13.

To a stirred boiling mixture of 35 parts of 4-fluoro-1,2-beolithium in 270 parts of dimethylbenoene was added. 57 parts of ethyl tert-dimethyl ethylbetoacetate in 90 parts of dimethylbenzoic acid are added dropwise over 2 hours, while the igniting water and the ethanol are separated (water separator). The reaction mixture is κ! ρ & Π. and the residue was crystallized with 2-propanol. The product was filtered off and purified by silica gel column chromatography using chloroform / methanol (98: 2 v / v) as eluent. Pure fractions were collected and the eluate was evaporated. There are thus obtained 11 parts of 6-fluoro-1,3-diyl-1- (1-methyl-2-phenylethenyl-22H-benoimidazol-2-one), m.p. 190 ° C.

Píklacll4. ·. To a stirred stream of 8.5 parts of 1,3-^1-Μ-1- (1-methylethenyl) -2H-benoimiitol-2-one in 45 parts of N / N-dimethylformamide was added dropwise 1.7 parts of sodium hydride (78% dispersion). ). ' After stirring for one hour at room temperature, the reaction mixture was stirred at room temperature. it is cooled to 0-5 ° C and 8.65 parts of 1-bromo-3-chloropropene is slowly added dropwise. Upon completion, stirring was continued for 3 hours at room temperature. The reaction mixture was poured into crushed ice and the product was extracted with toluene. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from 2-propanol to give 5.5 parts (44%) of 1-d-chloroprop-4-yl-1H-dihydro-1-C1-methlethenyl) -2H-benzimidpao-2-one, m.p. 115 ° C. '

Hatch 1 5 ‘.

To the stirred and hot (55 ° C) 22.2 parts of 1,3-β-β-5,6-Pimeethyl-3- (1-methenylphenylethenil) -2H-benoimidoool-2-one, 3 parts of Ν, Ν, Ν-trietlyl · benzenesilicon chloride and

112.5 parts of a 60% sodium hydroxide solution are added dropwise to 15.8 parts of 1-bromo-3-chloropropane (slight exothermic reactions). Upon completion, water is added and the oily product is extracted with toluene. The extract was dried and removed. The residue is crystallized from 2,2'-oxoxispropane and dried to give 25 parts (88.5%) of 1- (3-chloroproppl-1-1,3-dihydro-5 ₎ 6-dihydro-3- (1-yl). 1 H -2-phenylphenylthio-4 H -benzoimidazol-4-one, mp 98 ° C.

Example 16

Using the procedure of Example 15 and using equivalent quantities of the starting mtt.

1- (3-chloropropyl) -1,3-chloro-3- (2-propanol) -2H-benzimidazol-2-oo as a residue, 1- (3-chloro-2-methylpiperopropane-1,3-chloro) -3- (1-Methanol-phenol) -2H-benzimidazol-2-one as a residue.

1- (3-chloropropyl) -5-fluoro-1,3-dihydro-3- (1-lithium-phenolethenyl) -2H-benzimidazo-2-oo as an oily residue.

Ex. D. 17

A solution of 13 parts of 1- (3-chloro-propyl) -1,3-dihydro-3- (1-methyl-ethyl) -2H-beosimidazol-2-one in 6 parts of a hydrochloric acid solution and 40 parts of ethanol was stirred at room temperature for 2 hours. místnooti. The reaction mixture was evaporated and the solid residue crystallized from 2-o-propanol to give

9.5 parts (90%) of 1- (3-chloraroall ·) - _'1> Зpdilydoo-2H-2-beooiiidazol ouu, mp 115 ° C. χ **.

She added ''.

A mixture of 25 parts of 1- (3-chloro-propyl) -1,3-dihydro-5,6-diethyl-3- (1-methyl-2-phenylethenyl) -1H-benzimidazol-4-one, 165 parts of 6 N hydrochloric acid solution and 160 parts of ethanol are stirred and heated to boiling for 6 hours. The reaction mixture was evaporated and the residue was dissolved in trichloromethane. The solution was dried, filtered and evaporated. The residue is paretaryslated from a mixture of 2,2 &apos; -oxibitaropt and 2-aroaoolo, and thereafter. drying yielded 16 parts (94.7%) of 1- (3-chloropropyl) -1,3-dihydro-5,6-methyl-2H-benzimidazol-2-one, m.p. 140 ° C. '

Example 19> A solution of 18 ^{0 says} profiles 3 - [(2-ю ⁱ nitrophenyl) tilinoJ · - ¹ ~ to ^p TOOL in ^{200 says} ^ ec ^h methanol and ^{100 d} ílech 10 N hydrochloric acid is hydrogenated at normal pressure and at 50 ° C in 5 parts of 10% palladium on charcoal. Upon consumption of the calculated amount of hydrogen (3 moles), the hydrogenation was stopped. The catalyst was filtered off and the filtrate was evaporated. The residue (predominantly 3 - [(2-aminophenyl) amino) -4-propano! h ^ <^ ⁱ ^ ^{<^} <^ C ^ H _ <^ i ^: iΡ) to burst the in 500 parts of water. To this solution was added a solution of 88.8 parts of potassium isocyanate in 150 parts of water, and the whole was stirred and heated to boiling for 15 hours. The reaction mixture was cooled and the product was extracted. The extract was dried and evaporated. The residue is dissolved in 250 parts of boiling water, treated with activated carbon and recrystallized at a temperature of. The precipitate was filtered off and crystallized from 400 parts of water followed by crystallization from. ethyl acetate is obtained. 58 parts. 1,3-dihydro-1- (idotropoxypropyl) -2H-benyiptdozolo-one hydrate, mp 48 ° C and 65 ° C. .

To a solution of 52.5 parts of 1'-dihydro-1- (3-lyydroxryroyyl) -2H-benzimidazole-2-one hydrate in 200 parts of pyridine was added dropwise 63 parts of MeOH. The mixture was stirred and air cooled for 2 hours. pyridine - evaporated - and 500 parts of water were added to the residue and the precipitate formed was filtered off. Dissolve in 350 parts and dry with magnesium sulfate and water. The residue was recrystallized from 40 parts of toluene to give 25.5 parts of 1,3-dihydropyridine- (2- _tert- oxryropyl) -2H-benzimidazolepiperidine methanesulfonate, m.p. 118-120 ° C.

/. . '

To a solution of 0.5 parts of sodium in 40 parts of absolute ethanol was added cold 5.4 parts of 1,3-dihydrophyl- (3-hydroxyoxy) -2H-benzimidazolazole-2-methanesulfonate. The mixture was stirred until all solids had dissolved. The solution was further stirred and heated to boiling for 2 hours. After cooling, the reaction mixture was filtered from the inorganic fraction and the filtrate was evaporated. The residue was dissolved in 80 parts of toluene, boiled with activated carbon, filtered, and the filtrate removed again. The solid was washed with cold toluene and crystallized from 16 parts toluene. There were thus obtained 2.6 parts of 3,4-dihydroxy-2H- [1, 2'-oxazinophase, 2'-benzimidazole. mp 115.5-118.5 ° C. .

To a solution of 5.7 - 3.4 parts-dihyírVp2H- [j .З3 ^of 2Xj ^{of n} and o £ з 2-nJbenzlmidazvll in 80 parts of 2-propanone, - is paid 5.7 parts of iodomethane and the reaction stirred and heals for two hours 50 minutes. A second portion of iodomethane was then added and the reaction stirred for a further 2 hours 50 minutes. The solvent was evaporated and an oily residue was obtained - β-1,3-dihydro-1β ((1-pyridyl) -3-methyl-2 H -benzoimidazo-2β).

Example 20. '

A mixture of 84 parts of ethyl 4- (4-chloro-2-nitrophenyl) amino] -1-piperidinylbenzylate, 750 parts of 48% hydrobromic acid in water was stirred and heated to boiling for 4 hours. The precipitated product was filtered off, washed with water and petroleum (dried and dried to give 71 parts (81%) of N- (4-methyl-2-nitrenyl) -4-piperidinyl hydrobromide, mp 275 ° C). .

A mixture of 105 parts of 1- (3-methylpyrrolidin-1-yl) -1- (trimethyl-11-methyl-22H-benzimidin-2-yl), 71 parts of N- (4-chloro-2-nitrophenyl) -4-piperidinyl hydrobromide, 53 parts of sodium carbonate, 0.2 parts of potassium iodide and 320 parts of 4-methyl-2-pentanone were stirred and heated to boiling for 24 hours using a water separator.The reaction mixture was cooled, water was added and the layers were separated The organic phase was dried, filtered and 98.5 parts (100%) of 1- (3- [4- (2-methylphenyl) -propyl] -1-piperidopropyl-1,3-trans-3- (1-methyl ethenyl) - are obtained. 2-benzimidazol-2-one.

A solution of 98.5 parts of 1-pZ-44E (4-chloro-22-nitropheryl) flour-1-piperazinyl-1,3-dihydroxy- (1-methlethenyl) -2H-benzenimidanol-2-one in 360 parts of toluene was degassed with a saturated solution of hydrogen chloride gas. 2-prvpanoll. Oil is deposited after boiling. The supernatant was decanted and the residual oil was suspended in water. The suspension was poured into concentrated ammonium hydroxide solution and the product was extracted with toluene. The extract was dried, filtered and evaporated. The residue was crystallized from 4-methyl-2-pentane. The product from ^ l ^ ensures and dried, yielding 68 parts (75.5%) 1-23 "44 ^- E ⁽ '* 4' Chtov-2pnitrvfenyr) Nina <0- ¹ pylyerlíinrl} -yrvpylrp1,3pdlhydrv-2H- bennimidazolep2ponu.

A mixture of 21.5 parts of 1-43-4,4-2 (4-chloro-2-nitrophenyl) amino-1-ylpiperidin-1-yl-1,3-dihydrop-2H-benzimidazol-2-one and 240 parts of methanol is hydrogenated at normal pressure at room temperature with 5 parts of Ranneynic. After the calculated mnoísví hydrogen vdíiltrlje catalyst and the filtrate was evaporated, yielding 20 parts (100%) 1-43- ^ 4-.4 (2 - ⁴ пш1no- -chlvr ^phenyl) -p ^{y p} nminnVJ Pθгi ^s inrl] -prv ^p J r ^{l 1, 3-dl} p ^t l I'v ^yd ^ ² ^ HP ^b ENN rai ^{l d l} ^ ² yes .ponl in the form ^of residue.

PMcla d 2 1.

A mixture of 21.5 parts of 1 '(3- ^[ 4- ^[ (4-chloro-2-nitrophenylamino) -1-piperidinyl] propyl] -1,3-dihydro-2H-benzimidazol-2-one and 240 parts of methanol is hydrogenated under normal conditions. The catalyst was filtered off, the filtrate was evaporated to give 18.5 parts (100%) of 1- (3-).

evaporator. _ч

Example 1 a d 2 2

To the stirred mixture. 39.2 parts of 3- (2-nitrophenyl) amino-1-propanol. and 225 parts by weight of trichloromethane were added dropwise to 35.7 parts by weight of sulfinyl chloride (exothermic reaction, the temperature rose to 45 ° C). After completion, stirring was continued for 6 hours at room temperature. boiling point. The reaction mixture was evaporated to give 43 parts (100%) of N- (3-chloropropyl-2-chlorobenzamide) as a residue.

A mixture of 43 parts of N- (3-chloropropyl) -2-nitropheneenamlou, 47.8 parts of 5-chloro-1,3-dihydro-1- (4-piperidenyl) -HH-benzenesulphol-2-one, 30.3 parts * The N, N-diethylethanamine and 180 parts of N, N-dimethylacetamide were stirred and heated at 100 ° C for 6 hours. The reaction mixture was cooled and poured into 1500 parts of water. The precipitated product is filtered off, washed with water and 2,2'-oxybispoopane and dried. 64 parts (78.3%) of 5-chloro-1,3-dihydro-1- (1-33 '(2'-tropheyyamlieo) propyl) -4-plperidenyl] -HH-beezimidazol-2-one, m.p. 220 ° C, are obtained.

^MES 64 says ^profiles of ^{5-chloro-1, 3-d} ih ^yd ro- ¹ - ^ ¹⁾ [3- (2-eitrofee lεmino ^yl) propyl] -4-piperidinyl ieylJ ^{d-2H-benzimidazol-2-one} 200 parts methanol and 225 parts tetralydrourane are hydrogenated under normal pressure at a room temperature of 10 parts. Retloflickel catalyst. Once the calculated hydrogen was consumed, the catalyst was filtered off through hyllo-kieselguhr and the filtrate was evaporated. The precipitate was crystallized from a mixture of 2-propanol and ethanol. The product from ^ filtered and dried ztok ^s 4 s ^{2 d profiles (70.5%) of 1} ·) + ^j 1 ³ 3 ^N - ⁽² -aminofex ^NY.) -Amino-propyl ^{0 1} | -4 -plperi inyJJ ^d) 5-cch0rr dildro-1,3-2H-2-beezimldazol-2-one, mp 196 ° C.

Example 23

A mixture of 4.6 parts of 1- (3-chloropropyl) -1-α-dihydro-2H-benzylimidazol-2-one, 5 parts of 1- (p-Oluorophenyl) -1,3,8-triaotspiro 4,5 decan-4-one, 10 parts uhičitamu. sodium, 0.2 parts of potassium iodide and 80 parts of 4-meethy-2-pentanone were stirred and heated overnight. After cooling, the precipitated product is filtered off and ground twice in a boiling mixture of 4-methyl-2-peotanone and

2-propanol and then in boiling methanol. After filtration and crystallization from a mixture of N, N -diethyleneormamide and water, 4.5 parts of 8 - ([3- (1,3-flhydro-2-oxo-2H-biphenylphenyl) -yl) propyl] -1- are obtained. (4-Oluorophenyl) -1,3,8-triazasplro-34.5-decan-4-one, mp 215.4 ° C.

Example 24 'according to the procedure and using equivalent příkladu.23 mnooství starting matteiálů · the following compounds were prepared: ⁸ - (3- ^(6-chloro-2, 3 - ^^ () - 2 ^ ¹ ^ 0- benei.mtod ^{1 ) p} ro ^p yl ^j - - ^{(- 8} -triazaзplro £ 4 th, 5] ^{fekan-4-one-r} hfmiit lfát, mp 233 ° C * ¹⁾ (Oluorfe ^ ^-1) - ⁸ - [3- ⁽² ^ ^{3-dihydro-5-dimethylhexyl} l- ^yl-2-oxo-1 H benzirnidd azl- ^1-yl) - N 3 O ^p -trazzas ioo4h j ^ kkan-à-oo, mp 245.2 ° C ,

8- (3 ^p, 3 ^{-dihydro-2-oxo-3- (^} ^ р опу ¹⁾ - ¹ ^ Bene micta from ^about - ¹ -yl - ¹ гopy ^p l - ¹ - ^ oy] .- ¹ ^ £ triazasplro 4,5] dektn-4-oo, t .. t. 114 DEG C. 8- [3- (2,3-flhyfro-2-oxo-1H-bene0Ieiddaz0l1 -yD-pollen] -1 - £ 3- (trffluoreeth1l) Ofoyl] ^-1,3,8-p traoaa8 irq44,5f ^d ecto-4-oo, mp 198.2 ° C,

O3- 8- (2,3-dlh1fro-2-oxo-1H-bee e0mi dtzl ^d-1-yl) -. 1-propy1j -Oeoy 1-1 traazaspiro-3,8 '[4,5- d decan 4-oo, mp 228 ° C, 202550

8- [3- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -1- (4-fluorophenyl) -1. 3.,8-triaza ^- spiro [4.5 *] cm-4-in, mp 171.7 ° C,

8- p- (6-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl-1-phenyl-1,3,8-triioispiil, 5j decan-4-one Mp 255-256 ° C

1o (4-f] ^ u ^ ⁿ ^ ^ORFE].) Of ⁸ £ ^3oQ2, 3o ^d i ^hy ^] ^ i ^ -2-o] ^ (^ - ^ ⁰ ^ - ^ ⁰ - ^t r ⁱ ^ f ^u Oder ^{t hy} l ^{^)} - ^ ^1H -bbez ^of middzol 1- ^Oy -propyl} -1,3,8-triazaspioo44, jddekan-4-one, mp 259.7 ° C. "

8- (3- (2,3odihydroo2ooooo1H bbez0miidiooi1-yl) -propyl] -3-methyl-1-phenyl-1,3,8-triioispirlζ4 5] ^{to d} e ^al-4-one, m. P ,. 1Θ ⁶ ° C.

- (4- [1- (3-Chloro-phenyl) -8- (3- (2,3-dihydro-2-ooo-1H) -thiophene] -thio] -dioic acid; 1-yl) propyl-1,3, ^8-p triioas Iro. (4,5- d ^d e ^k ino4 ^- one, ^{m. p. 208.6} ° C and ^.

8- (3- (1H-benzimidazol-10-yl)) propyl] -1-phenyl-1,3,8-trioiaprop-44,5,5-decino-4-one; , t., t. .191 ° C.

Example 25

A mixture of 4.2 parts of 4-chloro-1,3-dihydropyrrole (2-hydroxypropyl) 2-benzoidazol-2-one methanesulfonate, 2.5 parts of 1-phenyl-1,3,8-triaspio-44,5-isomer-4-one 10 parts of sodium carbonate and 80 parts of 4-ethyl-2-ethylsulfate were stirred and heated to boiling overnight. The reaction mixture was cooled and water was added. The precipitated product is filtered off and twice with a mixture of Ν, Ν-dimethylformamide and water. Yielding 0.8 parts (17%) of 8- {3- (7-chloro-1,3ddiyydoo2Oooxo 2Hobenoo-indazol-1-yl) prlpylJo1-fezyl-1, 3, ⁸ -triaoissirl 04,5JdekiZo4olnu, mp 258.4 Deň: 32 ° C.

EXAMPLE 26 Following the procedure of Example 25 and carrying out the reaction in Ν, Ν-dimethylformamide as the solvent, the following compounds were prepared from the appropriate starting materials:

8- [α- (5-chloro-2,3-dilyrdro-2-oxo-1 H -benzimidazol-10-yl) -1-propyl] -1-fezyl-1,3. _J-8 ^J tiiiOissiil04,5 ldekino4ooz, mp ²³³ 7 ° C and '

8-03 '(2,3-dihydro-5-methylpyrrolidino-1H-benzimidazol-1-yl) propyl] -1-fezyl-1,3. ^{8-tiiižissiil-} 04,5j | dekino4ooz, mp 255.5 ° C.

Example · 2 · 7 ·

A mixture of 5 parts 1,3odiiydroo1o (3-lodprosylO-O-methyl-2 Hobenoimidaool ^2-2-one ·. · 3.4 parts of 1-fezyl-1,3,8-decane triaoissiil U ^^ ^ -one, 2.65 of sodium carbonate and 22.5 parts of N, N-dimethyl were stirred and heated at 70 ° C for two hours. The reaction mixture was cooled, poured into water and precipitated. The aqueous phase is decanted and the oil is drained in chloroform, the solution is dried, filtered and evaporated, and the residue is purified by silica gel column chromatography using a mixture of trichloromethane. 5% methanol as ^ · Optional EDL ^ ^ · pure fractions are collected and the eluent was o ^ J ^ p ^ i ^ her., yielding 1 part 8-03- (1,3odihydroo3ometlillo2-.oχoo benz0mi ^-2H-d diol-1-phenyl-1, 3-phenyl-1,3,8-triazaspiro ([delta] _J decahydase), mp 164.4 ° C.

Example · 28

A mixture of 8 parts of 5,6oPi1o-1,3-dihydil-1- (2-dihydrosysosyl) -2H-beaoimidiool-2-la methanesulflaate, 9.2 parts of 1-pheayl-1,3,8-triaspioo (4,5-deca-4-one, 90 parts) The Ν, Ν-dimethylformamide was stirred and heated at 60 ° C for one hour, the reaction mixture was evaporated and water was added to the residue, the mixture was made alkaline with ammonium hydrooid and the product was extracted with chloroform · The extract was dried, filtered · The residue is purified by silica gel column chromatography using a mixture of chloroform and 10% methanol, the pure fractions are combined and the eluate is evaporated off, and the solid is filtered and dried and treated with 2 parts of 8-03- (5,6-). dichloro-3-one _J-2-PiiyPil Loo-2H->. obenoiri ^d Daoo-1oyl) silpyll] -1-F9 ^ 1-1 3,8o · triazassiro44,5pdekaa-4-lauryl, t .. t. · 275., 2 · ° C ·

A mixture of 2,3 parts of 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one, 2,5-part-chloro-1,3-dihydro-1- (4-piperidinyl) -HH-enzimidazol-a-one, 3.2 parts of sodium carbonate, 0.1 parts of potassium iodide and 80 parts of 4-methyl-2-pentene are stirred and allowed to boil for 24 hours. The reaction mixture was cooled to room temperature and water was added. The undissolved product was filtered off and purified by silica gel column chromatography using a mixture of chloroform and 10% methanol as eluent, the pure fractions were combined and the solvent was evaporated. The residue was crystallized from 4-methyl-2-pentin-1. The product was filtered off and the product was filtered from a mixture of N, N-dimethytoramide and water to give 1,3-part (30%) of 5-chloro-1- (2-carboxylic acid). 1- [3 ^ "(1,3-dihydjo 2jOχj benzimidaaol-2H-1-yl) -prop ^P H] - ⁴ -p ^{r a} PoE din ^yl} - ^{1, 3-di hyd} r j-2H-benzimidazoj -2-JNU tt 24 ² 5 ° C.

Example 1 a d 3 0

Following the procedure of Example 29 and using equivalent mono-dry starting materials, the following was prepared:

5-Chloro-1- [1- {3- [2,3-dimethyl-3- (1-methyl-ethyl) -2-oxo-1H-beenimidazol-1-yl] -2-methoxy-phenyl} -4-piperidinyl] -4-piperidinyl -1, .alpha.-illdrdro-2b1-eonziriaa1b2-10 'in the form; olejjviééij rest,

6-chloro-1- (3- (4 - ('- chloro-2,3-dihydro-2-iodo-1H-eenzimidazol-1-yl) -1-benzoedioyl) -1,3-biphenyl} -2H-benzoimiaazol-2-oo hydrate , mp 179.6 ° C - (3-e 4- ^(2,3 · b i ^{ha di-2-rj} jχo- ^1H - ^e enoimidaaz ^{- 1-yl.)} - ¹ b i ^{on of the} eriaioplj- rj ^of PL- - ^1, 3 - ^. ^ 8γο 5 »6- <Ηmetthrl ^{eenoiLmradaiO-2H-2-one-2--orjpí} loját, mp 159 DEG;

6-Chloro o- ^{1, 1} - {3- [4- ^(2-oxo ^^^ Aro ^1H - ^e ENO ^from miaaai ^- - 1 - ^yl) - ¹ - ri ^^ ^ opj ^P ro 2'-2-y, mp 273 ° C,

- ¹ - £ 3-E 4- ^(2, 3- ^and even ^iha гj 2-jχo-1H-benz ^r AAAle ^{of II-1-b-l.)} - 1-p ^of guanine, ^and in ^{the p} Ц- rj ^{op (} l) - ^1- imidazol-2-one, mp 225 ° C,

1, 3- ^ 1 ^^ 0-1 - {3-E4- (2,3-biphenyl-2-yl-1H-eenoimidazo-1-yl) - 1 b0 ^of 0-triazoyl for 3'-trifluoromethyl) -2H-ethoxyimidazo-2-one, mp 263.4 ° C, ° C. - {3- [4- (2,3-B-2,3-dihydro-1H-benzo-1-yl) -1-benzotraanol] or-PO1} -1,3-411 ^ -2H-eenzimidazo-2 -jo, mp 253 and 2555 ° C,

-cMo on-1 - {3-Cl- C2> 3 ^and II-2 ^P-DDO jχo o3- (2-ρr peIoh.) -1H-benoiimi ^and aaiOl 1 -Ц oropo1 -44p0potrdib} • ^ l ] - ¹ , Zad ⁱ h ^d d1 ^{H2 H} Hb ^t Oiridazol-2-en ^, mp ^ ° C, '

- {3-C3,6-dihidro-4- (2,3-amino-2-iodo-1H) -ethoxyimido-1- (1-yl) -1H] -piperidin-1-yl} -1,3b - ^d ie ^hd rOb · 2 ^H - ^e tnzimi ^d aai ¹ -2-on, t. 206, ⁶ ° C, 5-chloro-r-1b £ l- {3- [2,3-4 ^{ζ 1ρ8ιό-3-} (1-τ ^p I ^p 1 ltthtn) -2- · -xo-1H-eenoimiadaz --1-hlJor-PP1} b4-0) · Otг оУ ^] - ^1, 3-diisobutyl ^ha -etožiriad2o ^H R2 ^- r2 - n tt · ¹⁶ 5 and ² .1- {ΐ- {4- (1H-benzenesulfon ^- azoi-1- ^[beta] - eutthyl] [ ^beta ] 4-oiotridine at ^[beta] -1,3-dihdr-2H-eenzimidaaz-2-one, mp - 157.1 ° C.

Example 31> -.

A mixture of 5.3 parts of 1- (3bCil-DPD-PP1) -1,3-5-diihadj ^{rethil-b-11-beta} Reth lethelorl) ^{-2H-1-eeozirida} ^ ^ 1-2-, 4.3 parts of 1 1,3-dihdd-1 · b (4-oeradrolidine) -benzene imidazol-2-one, 6.4 parts of sodium carbonate and 200 parts of 4-rttyl-2-pentimine were stirred and heated overnight, leaving to dissolve. water separators. After cooling, water is added and the layers are separated. The 4-methyl-2-foam-phase is dried, filtered and filtered. The oily residue was purified by chromatography on silica gel using a mixture of chloroform and methanol (90:10 by volume) as the eluent. - Čisté- phase - collecting eluate is evaporated - and yielding 6 parts (67%) of 1- {3-4- (2зЗadihyddo-2-oxo-H-etoiimib aařijl1-PL) on b1b0ioeriaioplj ^г -PPl- " 1.3 "a) i ^I j ^У г DR-51-methyl-3-l1-rttihlttieoyl) 2HH-etozimiaazo - 2-one as an oil. ·>

- Example 1 - a d 3 2

The following compounds were prepared according to the procedure of Example 31 - and using equivalent m-s of appropriate starting materials:

^1- [3-74- (5-chloro-2,3,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl] -1,3-dihydro-5-methyl- 3 - (1-methylethenyl) -2H-benzimidazol-2-one in the form of an olefinic residue;

3- {3- [4- (5-chloro-2,3'-dihydroxy-20-oxo-1H-benzimidimido-1-yl -) - 1-enenridinyl) propyl} -1,3-dihydro-5 methyl-1- (1-methlethynyl) -2H-benzimididol-2-yl in the form of an oily residue, ^1- {1- [3- ( ^1H -nitro-4-oxazol-1-yl) iroeyl] -4- piperidine-5-chloro-1,3-dihydro-2H-benzimidazol-2-ol, mp 224 ° C, o <

5-Chloo-1- (1- [3- (2-oxo-3 (2H) -benzoyl) oxoyl) iropell-4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-ol, mp 212.3 ° C. ·

Example 33

A mixture of 5.4 parts of 3- (3-bromo-propyl) -2 (3H) -benzylbiodolone, 4.5 parts of 5-chloro-1,3-dihydro-dro-1- (4-piperidinyl) 22H-benzimidol-2-one 5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-orientonone were stirred and heated to reflux for 3 hours. using a water separator. After cooling. sn adds water and layers sn zoom out. The organic phase was dried, filtered and evaporated. The residue was crystallized from a mixture of 4-methyl-2-yentanoyl and 2-propayone. The product was filtered off and dried. 2.5. % (31%) of 5-chloro-1,3-diydool-1- {1- [3- (2-oxo-3 (2H) -benzosothiololyl) iropyl] -4-piperidinyl] -1H-benzimidazol-2-yl, m.p. mp 184.1 ° C.

Example 34

Following the procedure of Example 33, 1- {1-1- (11-H-beolriazol-11-yl-1-propyl-4-pipe) was prepared. 3-oyl, m.p. 203.4% by the reaction of 1- (3-bromopropyl-1 H -benzzialialol) with 5-chloro-1,3-diildro-1- (4-piperidinyl) - (2 H -endenimidazole-2-one).

Example 35,

A mixture of 5 parts of 1,3-dihydrs-1- (3-sodiumpropyl) -ethyl 2-2H-benidimidol-2-one, 3.75 parts of 5-chloro-1,3-dihydro-1- (4-piperidinyl) 22H-benzimifols1-2-dream uhličtténu 2.65 parts and 22.5 parts of sodium Ν _J Ν-sn dimethylformemifu stirred for two hours at 70 to 80 ° C. The reaction mixture is cooled, poured into water and the precipitated product is collected. The reaction mixture is used in the reaction. of chloroform, the solution is dried, filtered and evaporated. The residue was crystallized from 4-methyl-2-pentanone to give 3 parts (43%) of 5-chloro-1- {N - [3- (1,3-dihydro-10-methyl-2-oxo-2H-benldmdfalo) - 1-yl) 4'-piperidinyl-1'-1,3-dihydro-2H-bryzimidazol-2-one, mp 166.5 ° C.

Example 3. ·.

A mixture of 7 parts of 5-chloro-1,3-dihydro-1 - (- (1-diphenyl) propyl) 22H-benlimindazzl-2-one methanesulfonate, 5.5 parts of 5-chloro-1,3-diphenyl-1- (4) 5-Sodium carbonate and 63 parts of Ν, Ν-ddrthllOirmemif were stared in an oil bath at 50 and 60 ° C for two hours. The reaction mixture is not poured into water. The resulting product is filtered off, dried and dried. Purified by chromatography on a column with a mixture of chloroform and 10% methanol as elution. agent. The pure fractions were collected and the eluate was evaporated. The solid was crystallized from 4-methyl-2-methyl-methyl. The product was filtered off by adding a mixture of N, N-dimethylformamide and water. The product was re-filtered to a range in the mixture of 4-methyl-2-pentanone and a small amount of N, N-dimethylformamide was added. The sn solution becomes clear by filtration and the sn filtrate is concentrated to a 10-part volume. Kzocenttát is different! in methanol. The precipitated product was filtered off, dried, yielding 1.27 parts of 5-chloro-1- {3-C4- (5-chloro-1'-chloro-oxo-2H-bromoimidyl) -1-l-12-propyl-propyl- 1,3-dihyfro-2H-benzimidazol-2-one, mp 229-136 ° C.

Example3 7

A mixture of 7 parts of 1- (3-chloro-propyl-55-fluoro-1,3-fluoro-1- (1-methyl-2-phenyl-phenyl) -2H-benzimidazol-2-yl, 5 parts of 5-ethyl-1,3-fhydro-1-yl. (4-piperidyl) 22 H -benzimiphalol-2-one, 4.25 parts of sodium carbonate, 0.1 parts of potassium iodide, and 200 parts of methyl-2-pentyl-2-pent-2-yl The oyu was stirred and heated to boiling overnight. The mixture is cooled to room temperature, water is added and the phases are separated from 202550. The organic phase was dried, filtered and evaporated. The residue was stirred and heated overnight with a solution of 55 parts of a 6 N solution of hydrochloric acid in 40 parts of ethanol. Disconnect the solvent and dissolve the residue in water. The mixture was basified with ammonium hydroxide and the product was extracted with chloroform. The extract was dried, filtered and evaporated. The residue was purified by chromatography on a silica gel column using chloroform / methanol (95: 5 v / v) as eluent. The pure fractions were combined and the eluate was evaporated. The evaporator was converted to the hydrochloride in 2-propanol. The salt was filtered off and dried. 1.2 parts of 1- (3-E4- (5-chloro-2,3-dihydro-2-oxo-1 H -benzimidazol-1-yl) -1-piperidinyl) propyl] -5-fluoro-1,3-dihydro- 2H-benzimidazol-2-one hydrochloride hydrate, mp 250 ° C.

Example 38. .

Following the procedure of Example 37, the following were prepared: ⁴ .

5-Chloro-1- (1- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -ethyl] -4-piperidinyl} -1,3-dihydro-1 H- ro-2H-benzimidazol-2-one herniihydrt, mp 258 ° <Creakcí 1- (4-chloreutyl) -1 _J-3 dihyfro-3- (1-mitlhylethenll) -2H-eenzinidřzol-2-one with 5-chloro- 1,3-Phenyl-1- (4-piperidinyl) 2H-eenzimidazol-2-one, a.

1 '- {[1- (2,3-dihydro-2-oxo) -1-oxo-2-oxo] -2-oxo-2-oxo-2-oxo-2-oxo-1,2,3-dihydro-2'-ox (R) -4-piperidinyl-4-piperidinyl) -1- (4-hydroxy-1-methylmethyl) -2H-eenzimidazoo-2-one, mp 174.3 ° C, by reaction of 1- (3-chloropropyl) -1,3-dihydro-3- (1-methylthenyl) -2H-benzimidazol-2-one with 1- (1-methylthylethyl) -3- (4-piperidin) -2H-eenzimidazole-2- about him. ‘

Example · 39

A mixture of 6 parts of 1- {3- [4- (2,3-dihyfro-2-oxo-1H-betimidro-1-yl) -1-piperidyl} propyl} -1,3-fihydro-5-mityl --- (1-Methylethylll) -2H-eenzimifazol-2-one, 12 parts hydrochloric acid solution, 30 parts water and 40 parts ethanol are stirred for a short time at 50. ° C and then one hour at room temperature. . The reaction mixture was evaporated and the residue was crystallized from a mixture of 4-methyl-2-pentanone and 2-orropanol. The product was collected and dried. There were obtained 3.7 parts (40%) of 1- {3-C4- (2,3-fhydro-2-oxo-1H-enimino-1-yl) -1-ppperidinyl] -propyl) -1,3-dihydro-5-ol. -methyl-2H-eenzimidazole-2-sn hydrochloride hydrate, mp 251.4 ° C.

Example · 40 ·. '

Following the procedure of Example 39, the following compounds were derived from the following (1-methylethenyl) -testulated analogs:

5-chloro-1-thi-3- (2,3-dihydro-5-methyl-2-oxs-1H-betimidro-1-l) piperidin-4-piperazinyl} -1,3-furyl-2H -enenzimidazole-2-sn hydrochloride hydrate, mp 213.3 ° C,

5-chloro-1- (1- (3- (2,3-dihydro-6-methyl-2-oxo-1H-biphenyl-4-y-y)) -1) -poP1-4-piperidinyl-1,3 -dihydro-2H-eenzimidazol-2-one amine, mp 195.4 ° C, and

5-Chhos-1- {1- (3- (2,3-dihydro-2-oxo-1 H -benzimidazol-1-yl) -2-methylpropyl) -4-piperazinyl} -1,3-furo-2H-eenzimidazole -2-one, mp 244 ° C.

Example 41

A mixture of 38 parts of carbon disulphide, 6 parts of 1- (1 - (- (1 - (1 - (1) - (1) - amino) piperidin-4-piperidinyl-5-chloro-1,1'-dihydroxy-22H-) The mixture was stirred and heated to boiling for 24 hours, the reaction mixture was crystallized from ethanol, and the product was collected and recrystallized from a mixture of RN-dimethylformamide and water to give the title compound. 3 parts (45.5%) of N- (1- (3- (2,3-dihydrs-2-thioxo-1H-benzimidopholyl)) pspyl-4-piperetinyl] -1H-dihydro c-eenzimidazol-4-one, mp 266.6 ° C.

Example · · 42

A mixture of 4 parts of 1- (1- (3- N- (2-aminophenyl) pyrrolidine) (Isyl-4-piperidinyl) -1,3-fihydro-1H-benzimidazol-4-one, 6 parts of concentrated hydrochloric acid and 30 parts of formic acid are stirred and heated to boiling overnight, the reaction mixture is evaporated and water is added to the residue, the mixture is basified with dilute ammonium hydroxide solution and the product is extracted with chloroform. Olpearek crystallized from 4-methyl-1-2-pentanone.The product was filtered off and recrystallized from 2-propanol to give 1.1 parts (27%) of 1- {1- [3- ( 6-chloro-1H-benzimidazol-1-ylpropyl-4-piperidinyl-1,3-dihydro-2H-benzimidazol-2-one, mp 214.9 ° C.

A mixture of 20 parts of 1- {3- [4 - [(2-a-2-di-2-ol-2-ol-2-ol)] and a 2-ol-2-carboxylic acid; 1- (1-chloro-1-propyl-1,3-dihydro-2H-benzimidazol-2-one), 52 parts carbon disulfide and 120 parts ethanol were stirred and heated for 24 hours. The reaction mixture is filtered, the filtrate is evaporated, the residue is crystallized from 2-aropanol, the product is filtered off and recrystallized from ethanol to give 7.5 parts (34%) of 1- {3- £ 4- (4-chloro-2,3-dihydro-2-thioxo-1H-bbnoiIiiiafolo1-yl) -) 11papp _Γ rdfnyl] -proayl) -1,3-di1ydro benzirida-2H-tetrazol-2-oou , mp 25-4.3 ° 4.

Example. '44 -

Following the procedure of Example 43, 1- [3-E4- (2,3-dihydro-2-thiooxal-1 H -benzimidazol-11-yl) -1-paperflyylapoPlyl-11,3,3-dihydro-22 H -benzimidazol-2-oo, mp 2418 was prepared. 5-1-eeakcí CЗз {£ 44 (22 _and minoOennl) -N NOJ ^^ -piperazin-1-ynyl} -propyl-1--dihidro- ^ H- benzoimidazol ^ -one with carbon disulfide.

x Example · 45

Mixture 2.21. 1- {3 '[44-55-halo-2,3-dihydro-2-thioxo-1 H -benoimidazol-1-yl} -1,3-piperidinyl] propyl] -1,3-dihydro-2 H -benzimidazol-2-one, 0.71 The mixture was stirred at room temperature overnight at room temperature. The reaction mixture was quenched. evaporate. The residue was stirred with water and the product was extracted with chloroform. The extract was dried) filtered and evaporated. The evaporation residue was crystallized from 4-methyl-2-aaentaoo. The product was filtered off and dried, yielding 1.1. 1- [3- {4- [5-chloro-2- (methylthio) -1H-benzimidazol-1-yl] -1,1-piperidinoyl] propyl-1,3-dihydro-2H-benzimidazol-2-one, m.p. '196.1 ° 4. ·

Příklel46,

A mixture of 5 parts of 5-chloro-1- [1-33- (2-dimethyl-20-oxo-1 H -benzoylindol-11-yl) -popall-4-aparifioyl-1-yl] -1D-10H-benzoylphiazol-2-one, 10 parts of acetic acid anhydride and 90 parts of toluene are stirred and heated to boiling overnight. The reaction mixture was basified with dilute sodium carbonate solution. The phases are separated and the organic oasis is dried, filtered and evaporated. The residue was recrystallized from toluene. The product is filtered off and recrystallized. again from toluene. Yielding 4.5 parts of 3-5-řcetyl cllLor-1- £ 1-3-5 - řCcelyl-3, C-II] dydro-0-oxo-1H-1-benziiidřzol ^{II) p} ro ^py l ] -4-piperidinyl ^f d ⁰ yyl-- ^- F- ^lld r2-2Hbbonziií y ^{0 d l} iso - ² · -oou, mp 185.3 '· ⁴ °.

Example '47.

To a stirred solution of 1 part 5-chloro-1- (1-E3-11-Chloro-2-oxo-2H-benzimidazol-2-yl) propyl-4-piperazin-1,3-dilydro-2H-benzimidazol-2-one in 32 parts of ethanol, a solution of 0.35 part (i) of tartaric acid in 8 parts of ethanol is added. The reaction mixture was stirred. let it crystallize. The product was filtered off and dried to give the ethanol (5 ') - 5-chloro-1- (1,3,4-1,1-dilydro-220xo-2H-benzimidazol-1-yl) -propanol. Tartaric acid, 4-piperidinol-1,3-dihydro-2H-benzimidazol-2-one, m.p. 153.5 ° 4.

Example 1 a 'd' 4 8 _t

Mixed solution of 1 part. 5-Clloro-1- (11-33-11) -difluoro-2-oxo-22H-benzimidazol-11-yl) methyl-4-piperidin-1-yl-1,1-dihydro-2H-benzoidazol-2-ol in 20 parts ethanol gas saturation, 202550 30.

with hydrogen chloride. The resulting hydrochloride crystallizes out with stirring. The product was filtered off and dried, yielding 0.6 parts (53%) of 5-chloro-1- {li [3- (1,3-dilydro-2-oxo-2H-benzimidazolidinyl) propyl] -4-piperidinyl. 1 H -1,3,3-dihydro-2H 2-benzimidazol-2-one lydrocyl chloride hydrate, mp 195.7 ° C.

’. ' ' of

Example 4 9.

5-Chloro-1- (1-l) - (1,3-dihydride) solution (1, 2, 3, 4, 3, 4, 3, 4, 3, 4, 3, 4, 3). (I) piperidin-4-piperidinyl] -1,3-dihydroxy-2H-benzimidazolo-2-one in 40 parts of ethanol is acidified with a solution of hydrogen chloride in propan-2-ol, and the hydrochloride precipitates upon cooling and is crystallized. 1 part (83%) of 5-cllor-1- _{(1-l3o (1,3-debt ^{Y-2-oxo-2H-benzZmiidtzO 11-yl)} propyl)] - 4opiperi (liyyly11,3-dilyro022H -benzimidazolium ethanolate, X. t.

213.7 ° C. . ·

Example 1 a d 5 0.

10.2 parts of 5-chloro-1- [3- (213-dilydro-2-oxo-1H-Oenzazlidazolazol-1-yl) -1-propoxy] -1,4-piperidinyl] -1 H -benzimidazol-2-one are converted into the salt. with (+) tartaric acid in 100 parts of water at boiling point. The solution was treated with 0.5 parts of activated carbon and 0.2 parts of diatomaceous earth for 10 minutes. The mixture was then filtered through diatomaceous earth, the filtrate was filtered and an oily precipitate was obtained. The oily product solidifies by heating. The mixture was allowed to cool to room temperature and the reaction mixture was stirred at this temperature for three hours. The product is filtered off, washed with water and dried under vacuum 18. hours at 60 ° C. 10.24 parts (85.3%) of 5-chloro-10 were obtained. VoCЗ '- (213-dihldro-2-oxo-1 H -benzimidazol-1-yl) propyl] -2-piperidinyl} -1,3-dihydro-2 H -benzimidazole-2-oxo-CR-R *, R *) 1 (+) α213-di-di-cyclobutanedioate hydrate, mp 184.1 ° C, = + 5.13 ° (c = 1% CH 3 OH). ,>.

Example 51

A mixture of 6.7 parts of 5-cllor-1,3-dlУ ^y dr011- ^(3-y lprrcl POOP ^yl) -2HbbenziaiPtzol-2-one meehansulo sulfonate, 4.2 parts of 4- (4-cllorferyl) -4-pipeгidinolU1 3.2 parts of sodium carbonate and 32 parts. Opentanone was stirred and heated at 50-60 ° C for 1.5 hours. The reaction mixture was poured into an ice bath. The precipitated product is filtered off and dissolved in chloroform. The solution was washed with water, dried, filtered and evaporated. The solid residue was chromatographed on a silica gel column using chloroform and 10% methanol as eluent. The pure fractions were collected and the solvent was removed. The solid residue was stirred in a small volume of trichloromethane. The product was filtered and crystallized from 4-ethyl-2-pent-2-yne. 2 parts ^{(24%) 5 °} C ^llo r ^"1 -'33 ^{f-1 -; (4"} C ^{f l} lr en ^yl) -4-r ^LYD χy- ¹ -piperidin-ynyl)] for ^beta yl ^} - ^{1 d} .iai ázolo2oonu1 mp 190.8 ° C.

Example ^ d 52 '

A mixture of 3.58 parts of 1- (3-chloropropyl) -1,3-dihydro-5,6-dimethyl-1H-benziaidol-2-one 3.17 parts of 4- (4-chlorophenyl) -4-piperidin-1-yl uM.ičitanu 5.3 parts of sodium 0,2dílu potassium iodide and 160 parts 4oaeth lo2- ^y · pentanonu- was stirred and heated for 24 hours under pouuití separator for water. After cooling, water is added and the phase is treated with oPPdH. The organic phase is dried, filtered and evaporated. The residue was converted to methanol and 2-propanol. The salt was filtered off and dried. and yielding 1.7 parts of 1- {3-Γ4- (4-chlorophen ^{yl) -4-yl} lldroc l1lpPperidin ^yl)] pr p ^y l-L13-dilydr - 516oŮimeetlrlo2H benzimidPZolo2oon-hydrochloride, mp 260 Low: 14 ° C. . , '

Example 1, 5 3

A mixture of 2.3 parts of 1- (3ochlorpr-propyl) ^-1,3-d dlУy oo-2H-benziaidtzolo2-onu12,12 parts of 4- (4o -CLL ^rfen-yl) o4opiperidinolu.1 3.2 parts UH-ičitírnu sodium, 0.1 parts of potassium iodide and 80 parts of ^4-yl-aeth 2opentamonu was stirred and refluxed for 36 hours to boiling point. After cooling to room temperature, water is added and the phases are separated. The organic phase is dried, filtered and evaporated. The residue was purified by silica gel column chromatography using a chloroform mixture. and 10% methanol as eluent. Pure fractions were collected and the eluate was evaporated. The residue was crystallized from toluene to give 1 part (26%) of 1- (3-P- (4-chlorophenyl) -4-hydroxy-1-piperidinyl) propyl} -1,3-dihydro-2H-benzisaidazole-2. -one, mp, 134.2 ° C.

Example 54

Following the procedure of Example 53 and using equivalent amounts of the appropriate starting materials, the following compounds were prepared:

6-chloro-1- [3- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] propyl] -1,3-dihydro-2H-benzimidazol-2-one, mp 180.6 ° C 3- {4- [4-chloro-3- (trifluoromethyl) phenyl] -4-hydroxy-1-piperidinyl} propyl] -1,3-dihydro-2H-benzimidazol-2-one, mp 189.2 ° C, ₍

1- {3- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] propyl] -1,3-dihydro-3- (2-propenyl) -2H-benzimidazol-2-one, mp 141.3 ° C,

1- {4- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] butyl} -1,3-dihydro-2H-benzimidazol-2-one, mp 160.6 ° C, and

1- [3- (1H-benzimidazol-1-yl) propyl] -4- (4-chlorophenyl) -4-piperidinol, m.p.

Example.55. '

A mixture of 5 parts of 1- (3-chloropropyl) -1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazol-2-one, 3.9 parts of 4- (4-fluorophenyl) -4-piperidinol, 5 parts. 3 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone were stirred and heated to boiling for 48 hours using a water trap. The reaction mixture was cooled to room temperature, water was added and the mixture basified by addition of 15 parts of 60% sodium hydroxide solution. The phases were separated and the organic phase was dried, filtered and evaporated. The residue was purified by silica gel column chromatography using a mixture of chloroform and 10% methanol as eluent. The pure fractions were collected and the eluate was evaporated. The oily residue was dissolved in 2-propanone. The solution was acidified with 2-propanol saturated with hydrogen chloride gas and the reaction mixture was stirred for 15 minutes and heated to boiling. The solvent was evaporated and the resulting hydrochloride was dissolved in water. The free base is liberated in a conventional manner with dilute sodium hydroxide solution. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from toluene. The product is filtered off and dried, yielding 2.5 parts of 1- {3- [4- (4-fluorophenyl) -4-hydroxy-1-piperidinyl] -1H-propyl] -1,3-dihydro-2H-benzimidazol-2-one, mp 13.4 ° C.

Example 56

Following the procedure of Example 23 and using equivalent amounts of starting materials, the following compounds were prepared:

o-Dichloro-1- [1- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-ylpropyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole-2- on, mp 263.1 ° C, yield 13%;

5-bromo-1- [1- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -4-piperidinyl] -1,3-dihydro-2H-benzimidazole-2 -on monohydrochloride monohydrate, mp 292.3 ° C, yield 9%;

8- [3- (2,3-Dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -1- (3-fluorophenyl) -1,3,8-triazaspiro- [4,5] decane-4- mp, mp 237-244 ° C, yield 74%;

8- [3- (2,3-Dihydro-2-oxo-1H-benzimidazol-1-ylpropyl) -1- (4-fluoro-3-methylphenyl) -1,3,8-triazaspiro-4,5-decane -4-one monohydrate, mp 167.6 ° C, yield 59%;

8-L3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl-1- (3,4-dimethylphenyl) -1,3,8-triazaspirole, 5-decan-4-one hemihydrate, mp 185.9 ° C, yield 55%;

1- (4-bromophenyl) -8- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -1,3,8-triazaspiro [eta] &lt; 4 &gt; he monohydrate, mp 197.4 ° C, yield 68%;

5-chloro-3- {1- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -4-piperidinyl} -1,3-dihydro-4-methyl-2H-benzimidazole -2-one monohydrochloride monohydrate, mp 298.4 ° C, yield 20%; ¹ -I »-C3- (2,3-dihydro-2-oxo-lH-benzimidazol-1 -yDpropyl] -4-piperidinyl] -1,3-dihydro-5- (trifluoromethyl]) - 2H-benzimidazole 2-one monohydrochloride, mp 223 DEG C., yield 10%; ⁴

4-Chloro-3- [1- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one monohydrochloride dihydrate, mp 227.4 ° C, yield 11%;

1- [1- [3- (2,3-Dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -4-piperidinyl] -5-fluoro-1,3-dihydro-2H-benzimidazol-2-ene, mp 234 ° C, yield 37%;

5-chloro-1- {3- [4- (5-fluoro-2,3-dihydron-2-one-1H-benzimidazol-1-yl) -1-piperidinyl] propyl] -1,3-dihydrp-2H-benzimidazole -2-one hemihydrate, mp 219.1 ° C, yield 12%;

6-Chloro-1- {1- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazole-2- he monohydrochloride hemihydrate 2-propanoate, (2: 1), mp 256.2 ° C, yield 51%;

5-fluoro-1- {3- [4- (5-fluoro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl] -1,3-dihydro-2H-benzimidazole- 2-one monohydrochloride 2-propanoate (2: 1), mp 243.7 ° C, yield 31%;

1- {1- [3- (2,3-Dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -4-piperidinyl} -1,3-dihydro-5,6-dimethyl-2H-benzimidazole-2 -on, mp> 300 ° C, yield 48%.,

SUBJECT OF THE INVENTION

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of the novel 1- (benzazolylalkyl) piperidine derivatives of the general formula I R ³ (I) and pharmaceutically acceptable acid addition salts thereof, wherein R and R are each independently hydrogen, halogen, methyl or trifluoromethyl O O II č -S-C-, -O-C-, В is selected from the group consisting of divalent radicals -N (L) -C-, -NH-C-, -S-C-, -C? C-, №N- and -N = CH-, wherein L ₄ is hydrogen, methyl, aryl, 2-propenyl and 1-methylethenyl, and these divalent radicals are attached to the benzene ring by a heteroatom, are hydrogen or methyl, m and n are integers 1 or 2, and the -NA moiety is selected from the group consisting of: a) A (A). 33,. . 202550 where I? ⁴ is a hydrogen atom or mmthy1 and ^R and R are of ^{Instructions.} independently hydrogen, halogen, melty! or erefluoromethyl b) the rest of the formula. B (B) Wherein R 6 and R ⁷ are independently hydrogen, atom, -halo, methyl or. trefluoromethyl, Y. is. aomm kysuu or aomm sulfur, M is an aromatic alkyl having up to 4 aromatic carbon, this and the eluted line indicates that the double bond between carbon atoms 3 and 4 of the piperidine nucleus is optional, and when Y is a sulfur atom it is between carbon atoms 3 and a 4-piperidine core single bond. M is then a hydrogen atom,. c) a residue of formula C (C) Wherein R @ 1 and R @ 3 are each independently alkyl containing from 1 to 5 hydrogen atoms, halogen, C1-6 alkyl, trephloormethyl and carbon; d) a residue of formula D wherein Q RR ^ is a hydrogen atom in ^{the atom} log ^ ^ u or t r ^e f ^{l e} uorme ^hyl, and (D) ^R 'is a hydrogen ® ^ u or water. a logene atom, characterized by:. by reacting a compound of the general formula. II - (CH R ³ 2U- ^CH ~ <CH ₂ ) _n -X (II) 202549 34 ·. where в 'has the same meaning as the ones of B. mentioned above, except for -HH-C, (S) -, X is the corresponding reactive ester function derived from the corresponding alcohol and R1. R 3, R 3, m and n are as defined above with a compound of formula III '(III) wherein A' is as defined above, in an organic solvent, and optionally pharmaceutically acceptable salts are prepared. 2. A process according to item 11 for the preparation of 1,3-dihydro-2H-benzimidazol-2-one of formula IV '. . (IV) and pharmaceutically acceptable salts thereof, wherein. L is hydrogen, methyl 2-propenyl or 1-methylethenyl, R and R are each independently hydrogen, halogen, methyl or taifloomethyl, R- ¹ is hydrogen or methyl, and. the rest is selected. from the group comprising: ' a) zbytekOSecného formula A '(A *) ^kd E ATO R ^4; m leads ^to u ^b o meth ^ ·, TO R is hydrogen,. halogen or tri-chloromethyl; and R ⁶ . It is hydrogen, a trifluoromethyl .ne ^{b w h} ύomet ^yl b) - a residue of the general formula B '(B') 7 '8 wherein R' and 'R' are independently hydrogen, halogen, or trifluoromethyl and the dotted line indicates that the double bond between the 3 and 4 carbon atoms of the piperidine ring is optional; and (c) a radical of formula C ' (C ') where is hydrogen or halogen, r! ^ a is hydrogen or triHoormethyl characterized' by reacting a compound of formula V (V) wherein X i přistáná- reactive est ^ ei ^ OC ^and defined above with a compound of formula III with ^p at ^the INA derived, ^and the alcohol ^{R 1,} R ^2, R 'and L have HN (III) wherein A has. as defined above in a suitable organic solvent. <· 3. The process according to item 1, for the preparation of 5-chloro-1- [11- (3- ₎ -dildduo-oxo-2H-beosimidazol-1-yl) -propyl-4-piperidinyl] -1,3-dihydro -2H-benzimidazole and pharmaceutically acceptable acid addition salts thereof, characterized by reacting 1- (3-01110 ^ 1) -1.13- (4-hydro-1H-benzimidazole) 5-chloro-1,3-dihydro-1- (4-piperidinyl) -2H-eenzinylidazole-2-oneine, and optionally preparing a pharmaceutically acceptable acid salt. 4. The method of item 1, for the preparation of 8- [3- (1,3-dihydroxy-H-beeoimidazol-1-yl) propyl] -1- (4-fluorophenol) -1 _> 3, 8-triazaspiru-4,5-decahydro-4-one and its pharmaceutically acceptable acid addition salts, characterized in that 1- (3-chloropropyl) -1,3-dihydro-1H-benzimidazol-one is reacted with 1- (p-fluorophenyl) -1,3,8-triazaspir-4,5-deca-4-one, and optionally preparing a pharmaceutically acceptable acid salt. Srvrrop ^ afta., M p .. introduction 7. Most AND