DK154950B - METHOD OF ANALOGUE FOR THE PREPARATION OF 1- (BENZAZOLYLALKYL) -PIPERIDE INGREDIENTS OR THE PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS - Google Patents

Description

in

DK 154950 B

The present invention relates to an analogue and process for the preparation of novel 1- (benzazolylalcyl) piperidine derivatives or the pharmaceutically acceptable acid addition salts thereof. These derivatives or acid addition salts possess valuable antiemetic activity.

A number of benzazolylal cooler and indolylal cooler substituted piperidine derivatives are known and a number of aminoalkyl substituted benzazoles, some of which have pharmacological, e.g. antidepressant, anti-convulsive, antihistamine or antispasmogenic activity.

10 Compounds of this invention differ structurally from such known compounds due to the nature of the benzazole moiety and / or the substituted piperidine moiety, respectively.

A number of the aforementioned prior art compounds can be found in the following references:

Int. Pharmacopsychiat; 1968 (1), page 214; C.A., 64 »2093 b (1966); C.A. 72, 111466 (1970); C.A., 81, 120632 b (1974);

French Patent No. 2,042,321 (Derw. Fr. Week S 16, 20 Pharm., Page 12); and

Belgian Patent Specification No. 753,472.

DK patent specification 119,880 discloses compounds, e.g.

25 ° / -Λ »/ - \ 7" ~? / F / V C- (CH2) 3 -Nx) \ in spiperone 30 C6H5 with neuroleptic activity and activity against emesis. However, this compound is not suitable as antiemetic due to In contrast, they are made according to the invention

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2 connections far more specific.

The present analogue method relates to the preparation of novel 1- (benzazolylalcyl) piperidine derivatives of the following general formula 5

- (CH.2) m - “- (CH2) n-N A

<H> ^ (I) io R'_ r2]? and the pharmaceutically acceptable acid addition salts thereof, wherein R and R are each independently a group or atom in the form of hydrogen, halogen, C1-6 alkyl or trifluoromethyl, B is a bivalent group in the form of o -N (L) -C-, -sc-, -Ο-c-, -N = N- or -N = CH-, where L is a group or atom in the form of hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl or C 2 alkenyl and wherein the bivalent groups are bonded to the benzene nucleus via their hetero atoms, R 1 is a group or atom in the form of hydrogen or methyl, m and n are each an integer of 1 or 2 and the group is

-N

a) a group of the general formula -c * ".4

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3 wherein is a group or atom in the form of hydrogen or C1-6 alkyl, 6 and R and R are each independently a group or atom in the form of hydrogen, halogen, C15-alkyl or trifluoromethyl,

b) a group of general formula 5 Y

ΟΛ, 10 R7 R8 7 8 wherein R and R are each independently a group or atom in the form of hydrogen, halogen, C 1-6 alkyl or trifluoromethyl, Y is an atom in the form of 0 or S, M is a group or an atom in the form of hydrogen, Cj_g alkyl or Cj ^ alkylcarbonyl, and the dotted line means that the bond between the carbon atoms 3 and 4 in the piperidine nucleus is optionally a double bond, provided that when Y is S, there is a single bond between the carbon atoms 3 and 4 in the piperidine nucleus, in which case M is hydrogen, or c) a group of the general formula R9 4

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wherein R 9 is a group or atom in the form of hydrogen, C, R-alkyl or IO 1-0 trifluoromethyl, and R is an atom in the form of hydrogen or halogen and the process is characterized by the characterizing part of claim 1.

"Lower alkyl" is presently straight or branched and has from 1 to 5 carbon atoms, such as e.g. methyl, ethyl, propyl, 1-methylethyl, butyl, pentyl and the like, "lower alkenyl" may be a straight or branched alkenyl radical having from 2 to 5 carbon atoms, such as e.g. 1-methylethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-10 pentenyl and the like, and the term "halogen" is common to atomic halogens less than 127, i.e. fluorine, chlorine, bromine and iodine.

The compounds of the general formula (I) R3 µ R1 R2 · 20 12 3 wherein R, R, R, m, η, B and -N ^ A have the previously mentioned meanings are conveniently prepared by reaction of a suitable reactive ester, having the general formula (II) wherein X is an appropriate reactive ester functional group derived from the corresponding alcohol, e.g.

25 is halogen, methanesulfonyl and 4-methyl benzyl sulfonyl, with a suitable piperidine derivative having the general formula (III) wherein -N 2 A is as defined above.

30 ^ T ^ ", n (j (XII) 35 E1 Rz (II) 5

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The foregoing condensation reaction is preferably carried out in a suitable organic solvent such as e.g. a lower alkanol, e.g. methanol, ethanol, propanol, butanol and similar alcohols, an aromatic hydrocarbon, e.g. benzene, methylbenzene and dimethyl benzene, a ketone, e.g. 4-methyl-2-pentanone, an ether, e.g. 1,4-dioxane and 1,1'-oxybisethane, Ν, Ν-dimethylformamide and nitrobenzene. The addition of a suitable base such as e.g. an alkali or alkaline earth metal carbonate or hydrogen carbonate can be used to collect the acid which is released during the course of the reaction. A small amount of a suitable metal iodide, e.g. sodium or potassium iodide, can be added as a reaction activator, especially when the reactive ester of formula (II) is a chloride.

Slightly elevated temperatures are suitable for speeding up the reaction rate, and preferably the reaction is carried out at the reflux temperature of the reaction mixture. In this and the following methods, the reaction products are separated from the medium and further purified, if necessary, using known methodology.

Compounds of formula (I) which may be denoted by the general formula 20 O 3 M - R

HN ^ N- (CH2) ra-CH. (CH2) n-N ^ A

(I-h) wherein R, R, m, n, R and -N ^ A have the meanings previously stated, 30 can also be prepared from the corresponding compounds of general formula (IV)

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6 O r 3 P-N 2 - - CH 3) -CH- (CH-) A.

5 - - (IV)

VV

R1 is R 10 wherein P is an appropriate protecting group by removing this protecting group according to technically known conventional methods.

Examples of such protecting groups include, among others, lower alkoxy-carbonyl, 4-methylbenzenesulfonyl, methanesulfonyl and preferably a substituted ethenyl group of general formula R 12 -CH-C-R 11 11 20 wherein R is C 15 alkyl and R is hydrogen, C1-6 alkyl or phenyl.

When the protecting group is lower alkoxycarbonyl, 4-methylbenzenesulfonyl or methanesulfonyl, it can be easily removed by alkaline hydrolysis and when the protecting group is a substituted ethenyl group, it is conveniently eliminated by exposure of the appropriate intermediate (IV ) for acid hydrolysis.

In performing this acid hydrolysis to remove the substituted ethenyl group from (IV), a wide range of protonic acids, including mineral acid such as e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric and phosphoric acid, and organic acids such as e.g. acetic acid and propionic acid. Furthermore, the addition may be carried out in reaction-inert organic solvents which are usually used in such type of hydrolytic reactions, e.g. methanol, ethanol and 2-propanone.

Compounds of formula (I) which may be denoted by the general formula

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7 O 'r3 \ _ /', (CHE) m ^ H- (CH2) nN / ~ NA '5 ^ (I_C) R1 R2 10 wherein R1, R2, m, n, R3 and -N ^^ A have the previously mentioned meanings, and B2 is a group in the form of -NH-C (O) - or -N = CH-, can be prepared by exposing a suitable benzene diamine having the formula (V) to ring closure with a suitable ring closure agent, the nature of which depends on the nature of B in the desired product.

Ϋ ^.

Η N, NH- (CH_) -CH- (CH_) -N A Ring- 2 \ _ / x 2'm 2 n at the end x (I-c) 2 ° 1 '2 (v) R1

The aforementioned cyclization reaction can be carried out according to technically known processes for the preparation of 1H-benzimidazoles and 1,3-dihydro-2H-benzimidazol-2-ones, from 1,2-benzene diamines. Suitable cyclization agents which can advantageously be used to prepare 2 compounds (I-c) wherein B stands for -NH-C (O) - include, for example, urea, carbonyl dichloride and alkali metal isocyanates, and the cyclization reaction can be carried out according to methods generally known in the art.

For example, is readily obtained when urea is used as a cyclizing agent, the desired compounds by stirring and heating the reactants together in the absence of any solvent.

When B stands for -N = CH-, formic acid or an appropriate tri (alkyloxy) methane can be used as the cyclizing agent.

35 Following a similar procedure to that described above, compounds of the general formula can be prepared

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8

R3 / - \ yH U

<- (CH2) m-CH- (CHr) nN ^ y (N, C- yu y- / (id) R1 R2 R7 R8 wherein R *, R2, R3, R7, R8, m, η, B and Y have the aforementioned meanings, by cyclizing a suitable benzene diamine having the general formula (VI), with a suitable cyclizing agent.

_ f / - \ h Bv_N- (CH2) m-CH- (CH2) n-N_ ^ y - u-closure \ (1-d) r1 r2 r7 r8 (VI) 20

In carrying out said cyclization reaction, the same cyclizing agents as described above can be used in the preparation of compounds (Ic) from compound (V), more particularly for the preparation of compounds (Ic), wherein B represents -NH-C ( O) -, or carbon disulfide.

Compounds of the general formula ^^ H '^ R1 rZ / 1 R8 wherein R1, R2, R3, R7, R8, m, n and B have the meanings previously stated and M1 is C1-6 alkyl or C1-5. all carbon carbonyl may be prepared 9

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by N-alkylation or N-acylation, respectively, of the corresponding unsubstituted compound with a suitable alkylating or acylating agent, according to technically known methodology. The N-alkylation can be e.g. is carried out by reacting the unsubstituted compound with a suitable, 5 from a suitably lower alkanol derived reactive ester, e.g. a halogen lower al can, or a lower alkyl methanesulfonate or -4-methylbenzenesulfonate under similar conditions as described above for the preparation of compound (I) starting from (II) and (III). The acylation can be carried out by reacting the unsubstituted compound with an anhydride or acyl halide, derived from the appropriate lower alkyl carboxylic acid according to technically known standard N-acylation processes.

When B in compounds (I-f) stands for -NH-C (O) -, it is appropriate to start from a suitable compound of general formula 15

H? 3. / -> H O

R12-CH = C-N '^ N- (CH2) m-CH- (CH2) n-N ^ J) (N ^ VNH

. . "" To H.

1 2 X = A

r1 R 7 8 I

R 'R

which is then N-alcylated or N-acylated as described above, respectively, after which the protective substituted ethenyl group is removed by acid hydrolysis.

The compounds of the general formula (If) wherein B stands for -N (L) -C (O) - wherein L is a lower alkyl or lower alkyl carbonyl radical identical to M is prepared starting from an appropriate compound in which Y stands for 0, by all cooling and acylation of both 1H-benzimidazole groups therein in one reaction step.

The starting materials used in the foregoing methods can be obtained by the methods described below.

Reactive esters of the general formula (II), which may be denoted by the general formula

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x x x x R3 a'- CH) -CH- (CI!) -X / cm Z'n (Il-a) R1 R2 12 3 2 wherein R, R, R, m, η, B and X have the previously mentioned meanings, 10 may be prepared as follows.

An appropriately substituted 2-chloro nitrobenzene of the general formula (VIII) is reacted with an appropriate aminoalkanol (IX) by heating under reflux of the reactants together in a suitable reaction-inert organic solvent, such as, for example. a lower alkanol, e.g.

15 ethanol, 2-propanol and butanol to give a [(2-nitrophenyl) amino] alkanol of the general formula (X), which is again subjected to a nitro-1-amine reduction, e.g. by catalytic hydrogenation using Raney nickel catalyst. The [(2-aminophenyl) amino] alkanol thus obtained of the general formula (XI) is then reacted with a suitable ring closure agent as described above for the preparation of the compounds (Ic) starting from (V) and the thus obtained alcohol (XII) is then converted to the desired reactive ester (II-a) using technique known in the art.

Halides are conveniently prepared by reacting (XII) with a suitable halogenating agent such as e.g. sulfinyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus pentabromide and phosphoryl chloride.

When the reactive ester is an iodide, it is preferably prepared from the corresponding chloride or bromide by replacing this halogen with iodine. Other reactive esters such as methanesulfonates and 4-methylbenzenesulfonates are obtained by reacting the alcohol with a suitable sulfonyl halide, such as e.g. methanesulfonyl chloride and 4-methylbenzenesulfonyl chloride, respectively.

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

35 11

DK 1 5 4 9 5 O B

° ZNWC1 'R3 + H2N- (CH2) m-CH- (CH2) n-OH | (VIII) R3 0 "N NH- (CH_) -CH- (CH-) -OH H" / RaNi 2 \ j '2 etc. Vtl 2 _y / R1 R2 (X) R3 H2N NH- (CH2) m-1H- (CH2) n-OH / cyclization ^ R ^ 2 (XI) R3 Ό * B ^ f- (CH2) m-CH- (CH2) n-QH reactive ester formation (Na ) rJr2 R _ (XII)

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12

Intermediates of formula (II), which may be denoted by the general formula 5 / $ ~ \ f

B N- (CH2) m-CH- (CH2) n-X

ISLAND

R> R2 10 12 3 3

wherein R, R, R, m, n and X have the meanings previously stated, and B

is a group in the form of -SC (O) -, -O-C (O) -, -N = N-, -N = CH- and -N (L *) - C (O) - wherein L1 is Cj_-alkyl, Cssken alkenyl or Cj_ alkyl alkylcarbonyl can also be conveniently prepared by introducing the reactive ester side group into a starting material having the general formula

B ^ NH

$ R1 R2 25 by techniques known in the art. Eg. one can first introduce a hydroxyalkyl chain by N-alkylation of (XIII) with a suitable halo-alkanol having the general formula (XIV) following ordinary N-alkylation processes to obtain an alcohol having the general formula (XV), the hydroxyl group is then converted to a reactive ester group by conventional methods, as previously described.

Instead of the halogenal cannula (XIV), a tetrahydro-2H-pyran-2-yl ether derivative thereof can also be used, in which case the corresponding ether derivative of (XV) is obtained if the ether function is split by acid hydrolysis, i.e. by stirring and heating the ether compound in diluted saline acid.

When the reactive ester (ΙΙ-b) is a halide, (II-b-1), it can

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Alternatively, 13 is prepared by reacting (XIII) with an equivalent amount of a suitable di halogenal can (XVI) in the presence of a suitably strong base such as e.g. sodium methanolate, or following a Mackosza process using aqueous alkali and a quaternary ammonium catalyst, e.g. Ν, Ν, Ν-triethylbenzene methanaminium chloride, to give the desired intermediate (II-b-1).

The foregoing method is further elucidated as follows.

R3 (XIII) + halogen (CH2) m -CH- (CH2) n-OH N-alkylation (XIV) / R

^ CH2> m- ™ - (CH 2) n ° H

ft. reactive ester formation ^ (Il-b) R1 R2 (XV) 3

RJ

(XIII) + halogen- (CH2) m -CH- (CH2) n-halogen base ^^ "(CH2 ^ m'CH" (CH2 ^ n "halogen $ R. \ z (II-b-1))

Intermediates having the general formula 35

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14 O · 3

| l - R

✓fcv. IN

HN N- (CII_) -CH- (CHJ) -X \ / 2'mv 2'n '$ R1 R2 12 3 10 wherein R, R, R, m, n and X have the meanings previously stated, can still be prepared by introducing the reactive ester side group into a starting material having the general formula (XVII)

ISLAND

II

15 Ρ-Ν ^^ ίΗ; // \ (XVII) 1 '2'

- R R

Wherein P is an appropriate protecting group, as previously defined, and then elimination of the protecting group in the compound thus obtained (XIX) by technically known methods as described above. The introduction of the reactive ester side group can be carried out by similar procedures as those described above for introducing this chain into starting materials having the general formula (XIII). More particularly, a hydroxyalkyl chain may first be introduced, after which the hydroxyl group of the thus obtained intermediate (XVIII) is converted to a reactive ester group to obtain (XIX) or, when the reactive ester 30 is a halide, (ΧΙΧ-a), For example, this halide can be obtained directly by reacting (XVII) with an appropriate di halogenal can.

When the protective P is one which can be subjected to alkaline hydrolysis, e.g. a lower alkyloxycarbonyl, methanesulfonyl or 4-methylbenzenesulfonyl group, the N-alkylation reaction for introducing the hydroxyalkyl or haloalkyl chain, respectively, should be carried out under non-hydrolytic conditions, e.g. using an appropriate metal

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15 base, such as e.g. sodium hydride or sodium methanolate, in a suitable aprotic organic solvent, e.g. N, N-dimethyl formamide, N, N-dimethylacetamide or hexamethylphosphoric triamide.

The preceding reactions are more clearly illustrated in the following schematic arrangement 16

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° R3

(XVII) + (XIV) + -alkylation (}. ^ (CH.) -OH

'\ / 2 m 2 n f}

+ (XVI) AA

'i 2

R1 R

x ^ (XVIII) reactive ester formation I? * 3 ^ * 3 PN ^ C ^ N- (CH) -CH- (CH) -halogen PN ^^ N-iCH.) -CH- (CH_) -X \ / L · ml π \ / ό mc π y R1 R2 R1 R2 (ΧΙΧ-a) (XIX)

v In the elimination of P

O elimination of P

HN <CS1- (CH2) m-CH- (CH2) n-halogen ("" c) \ β R1 "R2 (II-c-1) 17

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Intermediates having the general formula 0 p3 'L il ^ n ^ n-ch -ch-ch -x 5 yj \ αι-d) R * R2 12 3 2 10 wherein R, R, R and X are as previously stated. meanings, and L is

Cj g alkyl alkyl or C₂_5 alkenyl, where this Cg ^-alkenyl is unsaturated at the δ, γ or 6 position, can be prepared as follows.

A suitable intermediate having the general formula (II-c) wherein m and n are each 1, (II-c-2) is treated with sodium metal in absolute ethanol, whereby a cyclic ether of the general formula (XX) is formed.

2

This is then reacted with a suitable reactive ester L X, (XXI) wherein and X have the meanings previously stated, e.g. by heating the reactants together under reflux in a suitable organic solvent such as e.g. 2-propanone to give the desired intermediate product (ΙΙ-d).

O 3 C

HN'CVN-CH - CH-CH, X i R1 ^ N .CV

\ _ / 2 2 1 "Ν <// λ ___Na v 2 D I 'i t

K, \) I Z 7 ^ RJ

y, _V absolute ethanol / 1 \ 2 \ R R j (XX) (II-c-2) S - * (II-d)

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18

The compounds of formula (IV), which are used as intermediates in the preparation of compounds (Ib), can generally be obtained by condensation reaction of an intermediate having the general formula (XIX) with a suitable intermediate having the general formula 5 ( III) under conditions similar to those described above for the preparation of compounds (Ia) when starting from (II) and (III).

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

10

The intermediates of formula (IV) wherein -Ν ^ 'Ά have the formula 15 - <rvH i

\ _ / VC NH

0, n K7 20 and designated as (IV-b) can still be prepared by condensing a suitable reactive ester having the formula (XIX) with a suitable N- (2-nitrophenyl) -4-piperidinamine having the general formula (XXII) followed by reduction of the nitro group of the compound thus obtained (XIII) by standard nitro-to-amine reduction methods, e.g. by reacting the nitro compound with hydrogen in statu nascendi or by catalytic hydrogenation in the presence of a suitable catalyst such as e.g. Raney nickel and cyclization of the resulting benzene diamine (XXIV) with an appropriate cyclizing agent, as described above.

The preceding turnovers are elucidated in the following schematic presentation.

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19 (XIX) + HN V 1 W NH NO2, R7 R8 (XXII) O '3

11 I H

P-N'C'N. (CH2) m-CH- (Cn2) n-N /) (f-i · 'w Nt {_ / ° 2 r ~ r2 ^ \ JR7 R8 \ (XXIII) O 3

II R

nitro-to-amine, P YC> - <CH2) m - <!; H- (CH7) n-N ~ X reduction * M W N "NH2 R ^ R2 / \ <R7 R8 4 (XXIV).

// ring closure v (IV-b)

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20

The starting materials herein of formula (XXII) may be prepared according to those of U.S.A. U.S. Patent No. 3,910,930.

The intermediates of formula (V) are obtained by condensing a suitable reactive ester having the general formula (XXV) with a suitable piperidine derivative having the formula (III), followed by reduction of the nitro group in the intermediate thus obtained (XXVI) to an amino group by standard nitro-to-amine reduction methods,. R 3 10 0, N NH- (CH 2) -iH- (CH 2) -X + (H 1) 2 v J 2 m 2'n '' ---- ^ R1_R2 15 '(XXV) R3 O ^ NA, nitro -to-amine ^ / / r (/ reduction 20 // \ / R1 R2 (XXVI) 25)

The reactive esters of formula (XXV) used herein as starting materials are readily prepared from an alcohol of formula (X) by converting the hydroxyl functional group thereof to a reactive ester group following standard procedures described herein.

The intermediates of formula (VI) can generally be prepared by condensing a suitable reactive ester having formula (II) with a suitable N- (2-nitrophenyl) -4 "piperidinamine having formula (XII) and subsequently reduction of the nitro group of the compound thus obtained (XXVII) to an amine group by standard nitro-to-amine reduction.

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21, as previously described.

It should be noted that when the nitro-to-amine reduction is carried out by catalytic hydrogenation using palladium-on-charcoal catalyst, dehalogenation may occur in compounds in which aromatic halogen substituents are present.

-. R3

(II) + (XXII) .- ^ B N- (CH) -CH- (CH) -N V

W 1 '2 n V_ / NH Noi & B' R7 R8 (XXVII) · Nitro-to-amine -—- (VI) reduction 20 The intermediates of formula (VII) can be similarly prepared by condensation of a reactive ester, which has formula (XXV), with a piperidine derivative having formula (XXII), followed by reduction of both nitro groups in the compound thus obtained (XXVIII) by standard procedures as previously described.

25 R3

(XXV) + (XXII) t I / - \ H

-> O N NH- (CH_) -CH- (CH-) -N Y

2 W 2 m 2 n V_y NH NO.

Q 'H1 κ · k2 M; (XXVIII) R7 R8 nitro-to-amine (VII) reduction

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22

Starting materials of formula (III), denoted by the formulas

/ - \ J ^ -N-R4 / —v II

5 a) HN_J b) HN

ά 'K

R5 R6 'R7 R8

(Ill-a) (Ill-b) I

15 X X

R 1 R 10 (III-c) 20 and processes for preparing the same compounds can be found respectively in the following patents: a) U.S.A. Patent No. 3,238,216, b) U.S.A. U.S. Patent No. 3,161,645, Belgian Patent No. 830,403, c) U.S.A. U.S. Patent No. 3,518,276 and U.S.A. Patent No. 3,575,990.

The starting material of formula (III), denoted by formula 30

/ - \ H S

HN X '>

N / C NH

35 R7 R8 (Ill-d) 23

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may generally be prepared from a suitable N- (2-aminophenyl) -4-piperidinamine having the general formula O Γ - \ / Η

5 (lower alkyl) -O-C-N Y

\ _ / NH NH

$ R7 R8 10 (XXIX)

The starting materials (III-d) are conveniently prepared by cyclizing (XXIX) with a suitable cyclizing agent, e.g. carbon disulfide, and subsequent removal of the lower all kyloxycarbonyl group in the compound thus obtained (XXX) by alkaline hydrolysis.

The N- (2-aminophenyl) -4-piperidinamines of formula (XXIX), a number of which are known compounds, can be prepared according to those of U.S.A. U.S. Patent No. 3,910,930 and Belgian Patent No. 830,403 disclosed 20 methods.

The foregoing methods are elucidated in the following schematic arrangement.

25 O

II H

(lower alkyl) -O-C-N Y

\ _ 'NH' NH

to 30 7 8

R R

(XXIX) 35 (XXIX) 24

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cyclization (lower alkyl) - OSN V II-V (III-d) \ _ / n'c "nh 'r' K8 / 15 The final starting materials of all the foregoing processes are usually known, or their preparation can be carried out by technical means. known methods for preparing similar compounds.

Eg. For example, the preferred starting materials of formula (XVII) wherein P is a suitably substituted ethenyl group, (XVII-a), of which a significant number are known compounds, can be prepared according to the methods described in J. Chem. Soc., 1960, p. 308 and p. 314.

More particularly, such compounds are conveniently prepared by the reaction of a suitable ester having the general formula (XXXII) wherein 12 and R have the meanings previously stated, with a suitable benzene diamine having the general formula (XXXIII). This reaction is preferably carried out by stirring and heating under reflux of the reactants together in a suitable reaction-inert organic solvent with azeotropic water removal. Suitable reaction-inert organic solvents for this purpose include, e.g. aromatic hydrocarbons such as benzene, methyl benzene and dimethyl benzene.

35

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25 -12 "R -CH-C-O- (lower alkyl) + ^^ v

^ 2 \ / 2 * J

5? = 0 · f ~ \ R11% J.

R1 R2 (XXXII) (XXXIII) in io; / o 12 µ R -CH = C— N ^ 'Vh,' 11 W / w R1_ R2 / 20 (XVII-a) / 25

The intermediates of formulas (V) and (VI) are considered novel and are useful intermediates in the preparation of the desired compounds of formula (I).

The compounds of the invention can be converted to their therapeutically useful acid addition salts by treatment with a suitable acid such as e.g. an inorganic acid such as haloacetic acid, e.g. hydrochloric and hydrochloric or sulfuric acid, nitric and phosphoric acid, or an organic acid such as e.g. acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamon acid, almond acid, methanesulfonic acid, ethanesulphonic acid, benzene sulphonic acid, 4-

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26 methyl benzenesulfonic acid, cyclohexanesulfamic acid, salicylic acid and 4-amino-2-hydroxybenzoic acid. Conversely, the salt form can be converted by treatment with alkali to the free base form.

The compounds of formula (I) and the therapeutically active acid addition salts thereof have been found to possess strong antiemetic activity, as evidenced by their ability to block apomorphine-induced vomitus in dogs. The method used is previously described 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 treated to elicit 1 hour thereafter with a standard dose of 0.31 mg / kg (subcutaneous) apomorphine.

The tables below give the EDgg values for a number of the considered compounds. The EDgg value here means the dose that protects 50% of the animals from emesis.

With respect to Danish Patent Specification No. 119,880, the preferred compound therein is a compound which is generically referred to as "spiperone".

This compound as well as the other compounds of the present Danish patent possess CNS depressant activity (i.e., neuroleptic activity). Such compounds are generally known to counteract apomorphine-induced emesis in dogs, and this property is generally used as a criterion for possible neuroleptic activity. The antagonism of apomorphine-induced emesis in dogs can be measured using the so-called "APO dog" test, which has been used to demonstrate the useful properties of the compounds of the present application.

Although spiperone possesses antiemetic properties, this compound is not suitable as antiemetic because of its lack of specificity. This specificity can be demonstrated by testing the compounds by the so-called "AP0 rat" test which detects CNS depressant activity and by the "APO dog" test which, as already mentioned, detects the ability to inhibit apomorphy-induced emesis. Obviously, a specific antiemetic compound will be active in the "AP0 dogs" test and inactive or only slightly active in the "APO rat" test. The "APO rat" test is performed as follows.

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27

The test animals used in the test are adult male Wistar rats (weight 240 ± 10 g). After overnight fasting, the animals are treated subcutaneously (1 ml / 100 g) with an aqueous solution of the compound to be examined (time = zero) and placed in separate observation cages.

At 30 minutes afterwards, 1.25 ml / kg apomorphine, hydrochloride (APO) is injected intravenously and the rats are observed for a period of 1 hour for the occurrence or absence of the following apomorphine-induced phenomena: anxiety and stereotypic chewing. In the present, the ED ^ values indicate the doses in mg / kg body weight that protect 50% of the animals against apomorphine-induced phenomena.

The following results are obtained for spiperone in the "APO dogs" and "AP0 rats" test: o SH5 20 "AP0 dogs" test "APO rats" test ED50 ED5q s.c.

0.00026 mg / kg 0.016 mg / kg 25

These results show that the reference compound has a distinct neuroleptic activity. In contrast, the compounds prepared by the process of the present application are far more specific. This is evidenced by the biological data in the enclosed tables, showing both the results for the "APO dogs" test and "AP0 rat" stones.

It is obvious that the compounds shown in the tables are listed for the purpose of exemplifying the anti-emetic properties elicited by all the compounds of formula (I).

28

DK 154950 B

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DK 154950 B

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31 DK 154950 B

TABLE IV

Compound ED ^ q mg / kg s.c.

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b H

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N + NvN- (CH), - Li Y 0.06

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H

DK 154950 B

32 In view of their useful antiemetic activity, the subject compounds may be formulated in various pharmaceutical forms for administration purposes. For the preparation of pharmaceutical compositions, an effective antiemetic amount of the particular compound, 5 in base or acid addition salt form, is combined as the active ingredient in close admixture with a pharmaceutically acceptable carrier, which carrier can take many different forms depending on the formulation desired for administration. . These pharmaceutical compositions are desirable in unit dosage form, preferably preferably for oral, rectal or parenteral injection. Eg. For example, for the preparation of the compositions in oral dosage form, any of the usual pharmaceutical media may be used, such as e.g. water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions, or solid carriers such as starches, sugar species, kaolin, lubricants, binders, disintegrants and the like in the case of powders , pills, capsules and tablets. Because of the convenience of administration thereof, tablets and capsules constitute the most useful oral dosage unit form, in which case solid pharmaceutical carriers are naturally used. For parenteral preparations, the carrier will usually comprise sterile water, at least in large part, although other ingredients, e.g. to aid in solubility may be included. Injectable solutions may e.g. are prepared wherein the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be used. Acid addition salts of (I) are obviously more suitable for the preparation of aqueous preparations because of their increased water solubility relative to the corresponding base form.

It is especially useful to formulate the aforementioned pharmaceutical compositions in dosage unit form for convenience in administration and regularity in dosage. In the specification and claims herein, dosage unit form means physically separate units which are suitable as unit doses, each unit containing a predetermined amount of active ingredient intended to produce the desired therapeutic effect with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including slotted or coated)

DK 154950 B

33 tablets), capsules, pills, powder letters, cachets, injectable solutions or suspensions, teaspoons, tablespoons and the like, and divisible multiples thereof.

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

The following formulations exemplify typical antiemetic dosage unit formulations suitable for systematic administration to animal and human subjects in accordance with the present invention.

Oral drops

The following formulation provides 50 liters of an oral drop solution containing 10 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 (AI) per ml.

A. I. 500 grams of lactic acid 0.5 liters of sodium saccharin 1750 grams of cocoa flavor 2.5 liters of purified water 2.5 liters of polyethylene glycol q.s. ad 50 liters 25 The active ingredient is dissolved in the lactic acid and 1.5 liters of polyethylene glycol at 60-80 ° C. After cooling to 30-40 ° C, 35 liters of polyethylene glycol are added and the mixture is stirred well. Then, a solution of the sodium saccharin in 2.5 liters of purified water is added and with stirring the cocoa flavor and polyethylene glycol q.s. by volume.

The resulting solution is filled into suitable containers.

Injectable solution

The following formulation provides 20 liters of a parenteral solution containing 2 mg of 5-chloro-1- {1- [3- (2,3-dihydro-2-oxo-1H-35-benzimidazol-1-yl) propyl] -4 -piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one as the active ingredient per ml.

34

DK 15495GB

A. I. 40 g tartaric acid 20 g methyl 4-hydroxybenzoate 36 g propyl 4-hydroxybenzoate 4 g 5 water for injection q.s. ad 20 liters

The methyl and propyl 4-hydroxybenzoates are dissolved in about 10 liters of boiling water for injection. After cooling to about 50 ° C, 10 is added tartaric acid and then the active ingredient. The solution is cooled to room temperature and replenished with water for injection q.s. by volume. The solution is sterilized by filtration (U.S.P. XVII p. 811) and filled into sterile containers.

15 Oral solution

The following formulation provides 20 liters of an oral solution containing 5 mg of 5-chloro-1- {1- [3- (2,3-dihydro-2-oxo-1H-benz-imidazol-1-yl) propyl] -4 -piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one as the active ingredient per teaspoonful (5 ml).

20 A.I. 20 g tartaric acid 10 g sodium saccharin 40 g glycerol 12 liter 25 sorbitol 70% solution 3 liter methyl 4-hydroxybenzoate 9 g propyl 4-hydroxybenzoate 1 g raspberry essence 2 ml gooseberry essence 2 ml 30 purified water q.s. ad 20 liters.

The methyl and propyl 4-hydroxybenzoates are dissolved in 4 liters of boiling purified water. In 3 liters of this solution, the tartaric acid is dissolved first and then the active ingredient. The latter solution is combined with the remaining portion of the former and the glycerol and sorbitol solution added thereto. The sodium saccharin is dissolved in 0.5 35

DK 154950 B

liter of water and the raspberry and gooseberry essences are added. The latter solution is combined with the former, water is added q.s. by volume and the resulting solution is filled into suitable carriers.

5 Coated Tablets 10,000 compressed tablets each containing as the active ingredient 10 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 is prepared according to the following formulation:

The tablet core A.I. 100 g 1actose 570 g starch 200 g 15 polyvinylpyrrolidone (Kollidon® K 90) 10 g microcrystalline cellulose (Avicel®) 100 g sodium dodecyl sulph 5 g 20 hydrogenated vegetable oil ("Sterotex") 15 g

Coat methyl cellulose 25 (Methocel® 60 HG) 10 g ethyl cell lul ose (Ethocel® 22 cps) 5 g glycerol 2.5 ml polyethylene glycol 6000 10 g 30 concentrated color suspension 30 ml ("Opaspray Kl-210") polyvinyl pyrrolidone ( "Povidone" 5 g magnesium stearate 2.5 g 35

DK 154950 B

36

Preparation of the tablet core

A mixture of the active ingredient, lactose and starch is well mixed and then wetted with a solution of the sodium dodecyl sulfate and polyvinyl pyrrole idone in about 200 ml of water. The wet powder mixture 5 is sieved, dried and sieved again. Then, add the crocrystalline cellulose and the hydrogenated vegetable oil. It all mixes well and compresses into tablets.

Coating 10 To a solution of methyl cellulose in 75 ml of denatured ethanol is added a solution of ethyl cellulose in 150 ml of dichloromethane. Then 75 ml of dichloromethane and the glycerol are added. The polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The latter solution is added to the former and then the magnesium stearate, polyvinylpyrrolidone and concentrated color suspension are added and the whole is homogenized. The tablet cores are coated with the mixture thus obtained in a coating apparatus.

Suppositories 20 100 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 according to the following formulation: 25 AI 3 g tartaric acid 3 g polyethylene glycol 400 25 ml surfactant (Span®) 12 g 30 triglycerides (Witepsol® 55) q.s. ad 300 g

The active ingredient is dissolved in a solution of the tartaric acid in polyethylene glycol 400. The surfactant and triglycerides are fused together. The latter mixture is well mixed with the former solution. The mixture thus obtained is poured into molds at a temperature 37

DK 1 54950 B

of 37-38 ° C to form suppositories.

In the following examples, Examples 1-22 illustrate preparation of the starting materials and Examples 23-54 of the process of the invention. Unless otherwise indicated, all parts therein are in parts by weight.

Example 1

A mixture of 100 parts of 1-chloro-2-nitro-4- (trifluoromethyl) benzene, 10 90 parts of 3-amino-1-propanol and 200 parts of butanol is stirred and heated to reflux. Stirring under reflux is continued overnight. The reaction mixture is cooled and evaporated. Water is added to the residue and the whole is acidified with a hydrochloric acid solution. The product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The solid residue is crystallized from petroleum ether. The product is filtered off and dried to give 141 parts (100%) of 3 - {[2-nitro-4- (trifluoromethyl) phenyl] amino} -1-propanol.

Example 2 Following the procedure of Example 1 and using equivocal amounts of the appropriate starting materials, 3 - [(4-methyl-2-nitrophenyl) amino] -1-propanol is prepared as a residue, 3 - [(4,5- dichloro-2-nitrophenyl) amino] -1-propanol, m.p. 97 ° C and 3 - [(2-chloro-6-nitrophenyl) amino] -1-propanol as a residue.

25

Example 3

A mixture of 70 parts of 3 - [(4-methyl-2-nitrophenyl) amino] -1-propanol and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. After taking up the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated to give 54 parts (91%) of 3 - [(2-amino-4-methyl-phenyl) -amino] -1-propanol as a residue .

Example 4 A mixture of 141 parts of 3 - {[2-nitro-4- (trifluoromethyl) phenyl] amino} -1-propanol and 1200 parts of methanol is hydrogenated at normal pressure

DK 154950 B

38 and at room temperature with 15 parts Raney-nickel catalyst. After taking up the calculated 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) phenyl] -5amino} -1-propanol.

Example 5

Following the procedure of Example 4 and using equivalent amounts of the appropriate starting materials: 3 - [(2-amino-4,5-dichlorophenyl) amino] -1-propanol hydrochloride, m.p. + 185 ° C, 3 - [(2-amino-6-chlorophenyl) amino] -1-propanol as a residue and 3- [(2-amino-4-chlorophenyl) amino] -1-propanol as an oily residue.

15

Example 6

To a stirred and cooled solution of 54 parts of 3 - [(2-amino-4-methylphenyl) amino] -1-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 20 water. at a temperature below 10 ° C. After performing this, stirring is continued, first for 1 hour at room temperature and further for 24 hours at reflux temperature. After cooling to room temperature, the product is extracted with trichloromethane. The extract is washed with a hydrochloric acid solution 5%, dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone to give 19.5 parts (31%) of 1,3-dihydro-1- (3-hydroxypropyl) -5-methyl-2H-benz in methyl dazole. 2-on, m.p.

114.1 ° C.

Example 7 Following the procedure of Example 6 and using equivalent amounts of the appropriate starting materials: 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

DK 154950 B

39 5-Chloro-1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one, m.p.

148.3 ° C.

Example 8 To a stirred solution of 18.5 parts of 1,3-dihydro-1- (3-hydroxy-propyl) -5-methyl-2H-benzimidazol-2-one in 325 parts of dichloromethane is added 11.9 parts Ν, Ν-diethylethanamine. Then 11.5 parts of methanesulfonyl chloride are added dropwise (slowly). After performing this, stirring is 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, m.p. . 125 ° C.

Example 9

Following the procedure of Example 8 and using equivalent amounts of the appropriate starting materials: 3- (5,6-di chloro-2,3-di hydro-2-oxo-1H-benzimidazol-1-yl) propyl methanesulfonate as an oily residue, 3- (7-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propylmethanesulfonate and 3- (5-chloro-2,3-dihydro-2- oxo-1H-benzimidazol-1-yl) propylmethanesulfonate, m.p. + 140 ° C.

Example 10

A mixture of 30 parts of 1H-benzimidazole, 49 parts of 2- (4-chlorobutoxy) -tetrahydro-2H-pyran, 21 parts of potassium hydroxide and 200 parts of ethanol is stirred and heated under reflux overnight. The reaction mixture is cooled to room temperature, filtered and the filtrate is evaporated.

The residue is stirred in water and acidified with a dilute hydrochloric acid solution. It is all stirred and heated for 30 minutes in a water bath. After cooling to room temperature, the product is extracted with methyl benzene. The aqueous 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.

DK 154950 B

40

Example 11

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, 32 parts of sulfinyl chloride are added dropwise. Upon completion, the whole is 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 to give 14 parts (56%) of 1- (3-chloropropyl) -1,3-dihydro-5- (trifluoromethyl) -2H-benzimidazole. 2-one.

10

Example 12

Following the procedure of Example 11 and using an equivalent amount of a 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, m.p. 122 ° C and 1- (4-chlorobutyl) -1H-benzimidazole as an oily residue.

Example 13

To a stirred and refluxed mixture of 35 parts of 4-fluoro-1,2-benzenediamine in 270 parts of dimethyl benzene, a solution of 57 parts of ethyl acetylbenzene acetate in 90 parts of dimethyl benzene is added dropwise over a 2 hour period. while in the meantime it formed 25 water and ethanol one distilled off (water discharge). The reaction mixture is evaporated and the residue is crystallized from 2-propanol. The product is filtered off and purified by column chromatography over sieve in cage! using a mixture of trichloromethane and methanol (98: 2 by volume) as eluant. The pure fractions are combined and the eluent is evaporated to give 11 parts of 6-fluoro-1,3-dihydro-1- (1-methyl-2-phenylethenyl) -2H-benzimidazole "2-one, m.p. 190 ° C.

Example 14

To a stirred solution of 8.15 parts of 1,3-dihydro-1- (1-methyl-ethenyl) -2H-benzimidazol-2-one in 45 parts of Ν, Ν-dimethylformamide is added portionwise 1.7 parts of sodium hydride dispersion 78% . After stirring in 1

DK 154950 B

For 41 hours at room temperature, the whole is cooled to 0-5 ° C and 8.65 parts of 1-bromo-3-chloropropane are added dropwise (slowly). Upon completion, stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto crushed ice and the product is extracted with 5 methyl benzene. The extract is washed with water, dried, filtered and evaporated. The 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-one, m.p. 115 ° C.

Example 15

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 Ν, Ν, Ν-triethylbenzene methanaminium chloride and 112.5 parts sodium hydroxide solution 60% are added dropwise 15.8 parts l-bromo-3-chloropropane 15 (slightly exothermic reaction). Upon completion, stirring is continued for 5 hours at 55 ° C. After cooling, water is added and the oily product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2-oxybispropane to give after drying 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 16

Following the procedure of Example 15 and using equivalent amounts of the appropriate starting materials: 1- (3-chloropropyl) -1,3-di hydro-3- (2-propenyl) -2H-benzimidazol-2-one is prepared. as a residue, 1- (3-chloro-2-methylpropyl) -1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazol-2-one as a residue and 1- (3-chloropropyl) ) -5-Fluoro-1,3-dihydro-3- (1-methyl-2-phenylethenyl) -2H-benzimidazol-2-one as an oily residue.

Example 17

A solution of 13 parts of 1- (3-chloropropyl) -1,3-dihydro-3- (1-methyl-ethenyl) -2H-benzimidazol-2-one in 6 parts of hydrochloric acid solution and 40 parts of ethanol is stirred for 2 hours. room temperature. The reaction mixture

DK 154950 B

42 is evaporated and the solid residue is crystallized from 2-propanol to give 9.5 parts (90%) of 1- (3-chloropropyl) -1,3-dihydro-2H-benz-imidazol-2-one, m.p. 115 ° C.

Example 18

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 heated under reflux for 6 hours. The reaction mixture is evaporated and the residue is dissolved in trichloromethane. This solution is dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanol to give after drying 16 parts (94.7%) of 1- (3-chloro-propyl) -1,3-dihydro-5,6- dimethyl-2H-benzimidazol-2-one, m.p. 140 ° C.

Example 19

A solution of 180 parts of 3 - [(2-nitrophenyl) amino] -1-propanol in 200 parts of methanol and 100 parts of hydrochloric acid solution 10N is hydrogenated at normal pressure and at a temperature of 50 ° C in the presence of 5 parts of palladium-on-charcoal catalyst 10%. After taking up the calculated amount of hydrogen 20 (3 moles), the hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The residue (mainly 3 - [(2-aminophenyl) amino] -1-propanol, hydrochloride) is dissolved in 500 parts of water. To this solution is added a solution of 88.8 parts of potassium isocyanate in 150 parts of water and the whole is stirred and heated under 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 250 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, followed by recrystallization from ethyl acetate to give 58 parts of 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one hydrate, m.p.

48-65 ° C.

To a solution of 52.5 parts of 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one hydrate in 200 parts of pyridine is added dropwise 63 parts of methanesulfonyl chloride. The mixture is stirred and cooled in the air for 2 hours.

Evaporate the pyridine. 500 parts of water are added to the residue and the precipitate formed is filtered off. It is dissolved in 350 parts of trichloromethane. This

DK 154950 B

43 solution is dried over magnesium sulfate and evaporated. The residue is crystallized from 40 parts of methylbenzene to give 25.5 parts of 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one, methanesulfonate, m.p. 118-120 ° C.

To a solution of 0.5 parts of sodium in 40 parts of absolute ethanol is added 5.4 parts of 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one methanesulfonate in the cold. It is all stirred until all the solid dissolves. The solution is further stirred and heated under reflux for 2 hours. After cooling, the reaction mixture is filtered from some inorganic substance and the filtrate is evaporated. The residue is dissolved in 80 parts of methylbenzene, boiled with activated charcoal, filtered and the filtrate is evaporated again. The solid residue is washed with cold methylbenzene and crystallized from 16 parts of methylbenzene to give 2.6 parts of 3,4-dihydro-2H- [1,3] oxazino [3,2-a] benzimidazole, m.p. 116.5 to 118.5 ° C.

To a solution of 5.7 parts of 3,4-dihydro-2H- [1,3] oxazino [3,2-a] benzimidazole in 80 parts of 2-propanone is added 5.7 parts of iodomethane and the whole is stirred and stirred. heated at reflux for 2 1/2 hours. Then another portion of 5.7 parts of iodomethane is added and the whole is further stirred and refluxed for 2 1/2 hours. The solvent is evaporated to give 1,3-dihydro-1- (3-iodopropyl) -3-methyl-2H-benzimidazol-2-one as an oily residue.

Example 20

A mixture of 84 parts of ethyl 4 - [(4-chloro-2-nitrophenyl) amino] -1-25 piperidine carboxylate and 750 parts of hydrobromic acid solution 48% in water is stirred and heated under reflux for 4 hours. The precipitated product is filtered off, washed with water and petroleum ether and dried to give 71 parts (81%) of N- (4-chloro-2-nitrophenyl) -4-piperidinamine hydrogen bromide, m.p. 275 ° C.

A mixture of 105 parts of 1- (3-chloropropyl) -1,3-dihydro-3- (1-methyl-ethenyl) -2H-benzimidazol-2-one, 71 parts of 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 and heated under reflux for 24 hours under water discharge. 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-

DK 154950 B

44 N-Trophenyl) amino] -1-piperidinyl} propyl] -1,3-dihydro-3- (1-methyl-ethenyl) -2H-benzimidazol-2-one as a residue.

A solution of 98.5 parts of 1- [3- {4 - [(4-chloro-2-nitrophenyl) amino] -1-piperidinyl} propyl] -1,3-dihydro-3- (1-methylethenyl) -2H -benzimidazol-2-one 5 in 360 parts of methyl benzene is acidified with 2-propanol, which is previously saturated with gaseous hydrogen chloride. After boiling for a time, an oil precipitates.

The above phase is decanted off and the remaining oil is suspended in water. The slurry is made alkaline with a concentrated ammonium hydroxide solution. The product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried to give 68 parts (75.5%) of 1- [3- {4 - [(4-chloro-2-nitrophenyl) amino] -1-piperidinyl} propyl] -1,3-dihydro-2H benzimidazole-2-one.

A mixture of 21.5 parts of 1- [3- {4 - [(4-chloro-2-nitrophenyl) amino] -1-piperidinyl} propyl] -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 catalyst. After taking up the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated to give 20 parts (100%) of 1- [3- {4 - [(2-amino-4-chlorophenyl) amino] -1-piperidinyl} -20 propyl ] -1,3-dihydro-2H-benzimidazol-2-one as a residue.

Example 21

A mixture of 21.5 parts of 1- [3- {4 - [(4-chloro-2-nitrophenyl) amino] -1-piperidinyl} propyl] -1,3-dihydro-2H-benzimidazol-2-one and 240 parts of methanol are hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. After taking up the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated to give 18.5 parts (100%) of 1- [3- {4 - [(2-aminophenyl) amino] -1-piperidinyl} -propyl] - 1,3-dihydro-2H-benzimidazol-2-one as a residue.

30

Example 22

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

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N- (3-chloropropyl) -2-nitrobenzenamine as a residue.

A mixture of 43 parts of N- (3-chloropropyl) -2-nitrobenzenamine, 47.8 parts of 5-chloro-1,3-dihydro-1- (4-piperidinyl) -2H-benzimidazol-2-one, 30.3 parts N, N-diethylethanamine and 180 parts of Ν, Ν-dimethylacetamide are stirred and heated under reflux 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-1,3-dihydro-1- [1- {3- ( 2-nitro-phenylamino) propyl] -4-piperidinyl} -2H-benzimidazol-2-one, m.p. 220 ° C.

A mixture of 64 parts of 5-chloro-1,3-dihydro-1- {1- [3- (2-nitrophenylamino) propyl-4-piperidinyl} -2H-benzimidazol-2-one in 200 parts of methanol and 225 parts of tetrahydrofuran are hydrogenated at normal pressure and at room temperature with 10 parts of Raney nickel. After taking up the calculated amount of hydrogen, the catalyst is filtered off over "Hyflo" and the filtrate 15 is evaporated. The 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) amino] propyl} -4-piperidinyl] -5-chloro-1,3-dihydro -2H-benzimidazol-2-one, m.p. 196 ° C.

Example 23

A mixture of 4.6 parts of 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one, 5 parts of 1- (p-fluorophenyl) -1,3,8-triazaspiro [4 5] decan-4-one, 10 parts sodium carbonate, 0.2 parts potassium iodide and 80 parts 4-methyl-2-pentanone are stirred and heated under reflux overnight. After cooling, the precipitated product is filtered off, which is then triturated twice: first in a boiling mixture of 4-methyl-2-pentanone and 2-propanol, and then in boiling methanol. It is again filtered off and crystallized from a mixture of N, N-dimethyl formamide and water to give 4.5 parts of 8- [3- (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) - propyl] -1- (4- fluorophenyl) -1,3,8-triazaspiro [4,5] decan-4-one, m.p. 215.4 ° C.

Example 24

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

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46 8- [3- (6-Chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -1- (4-fluorophenyl) -1,3,8-tri azaspiro [ 4,5] decan-4-one, hemi hydrate, snip. 23 ° C, 1- (4-Fluorophenyl) -8- [3- (2,3-dihydro-5,6-dimethyl-2-oxo-1H-benzimidazol-1-yl) propyl] -1,3,8-tri azaspi ro [4,5] decan-4-on, snip.

245.2 ° C, 8- {3- [2,3-dihydro-2-oxo-3- (2-propenyl) -1H-benzimidazol-1-yl] propyl} -1-phenyl-1,3 , 8-triazaspiro [4,5] decan-4-one, m.p. 114 ° C, 8- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -1- [3- (trifluoromethyl) phenyl] -1,3,8- tri azaspi ro [4,5] decan-4-one, m.p.

198.2 ° C, 8- [3- (2,3-Dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -1-phenyl-1,3,8-triazaspiro [4,5 ] decan-4-one, m.p. 228 ° C, 8- [3- (5-Chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -propyl] -1- (4-fluorophenyl) -1,3,8- triazaspiro [4,5] decan-4-one, m.p. 171.7 ° C, 8- [3- (6-Chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one, m.p. 255-256 ° C, 1- (4-Fluorophenyl) -8- {3- [2,3-dihydro-2-oxo-5- (trifluoromethyl) -1H-benzimidazol-1-yl] propyl} 3,8-triazaspiro [4,5] decan-4-one, m.p.

259.7 ° C, 8- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -3-methyl-1-phenyl-1,3,8-triazaspiro [ 4,5] decan-4-one, m.p. 186 ° C, 1- (4-Chloro-3-methylphenyl) -8- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -1,3,8-triazaspiro [4,5] decan-4-one, m.p. 208.6 ° C and 8- [3- (1H-benzimidazol-1-yl) propyl] -1-phenyl-1,3,8-triazaspiro [4,5] -25 decan-4-one, m.p. 191 ° C.

Example 25

A mixture of 4.2 parts of 4-chloro-1,3-dihydro-3- (3-hydroxypropyl) -2H-benzimidazol-2-one, methanesulfonate, 2.5 parts of 1-phenyl-1,2,8-triazaspiro -30 [4,5] decan-4-one, 10 parts sodium carbonate and 80 parts 4-methyl-2-pentanone are stirred and heated under 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) propyl] -1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one, m.p. 258.4 ° C.

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47

Example 26

Following the procedure of Example 25 and carrying out the reaction in Ν, Ν-dimethylformamide as solvent, the following compounds are prepared from the appropriate starting materials: 5 8- [3- (5-chloro-2,3-dihydro-2-oxo-1H -benzimidazol-1-yl) -propyl] -1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one, m.p. 233.7 ° C and 8- [3- (2,3-dihydro-5-methyl-2-oxo-1H-benzimidazol-1-yl) propyl] -1-phenyl-1,3,8-triazaspiro [ 4,5] decan-4-one, m.p. 255.5 ° C.

Example 27

A mixture of 5 parts of 1,3-dihydro-1- (3-iodopropyl) -3-methyl-2H-benzimidazol-2-one, 3.4 parts of 1-phenyl-1,3,8-triazaspiro [4,5 ] decan-4-one, 2.65 parts sodium carbonate and 22.5 parts Ν, Ν-dimethylformamide are stirred and heated for 2 hours at 70 ° C. The reaction mixture is cooled and poured into water to form an oily precipitate. The above aqueous 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 over silica gel using a mixture of trichloromethane and 5% methanol as eluent. The pure fractions are collected and the eluent is evaporated to give 1 part 8- [3- (1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl) propyl] phenyl-1,3, 8-triazaspiro [4,5] decan-4-one, m.p. 164.4 ° C.

Example 28 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-Triaza-spiro [4,5] decan-4-one and 90 parts of Ν, Ν-dimethylformamide are stirred and heated to 60 ° C for 1 hour. The reaction mixture is evaporated and water is added to the residue. The whole is made alkaline with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using 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) propyl] -1-phenyl -1,3,8-tri aza-

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48 spiro [4,5] decan-4-one, m.p. 275.2 ° C.

Example 29

A mixture of 2.3 parts of 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one, 2.5 parts of 5-chloro-1,3-dihydro-1- (4) (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 heated under reflux for 24 hours. The reaction mixture is cooled to room temperature and water is added. The undissolved product is filtered off and purified by column chromatography over 10 silica gel using 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 off and recrystallized from a mixture of N, N-dimethyl formamide and water to give 1.3 parts (30%) of 5-chloro-1- {1- [3-15 (1,3-dihydro-2-oxo) -2H-benzimidazol-1-yl) propyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one, m.p. 242.5 ° C.

Example 30

Following the procedure of Example 29 and using equivalent amounts of the appropriate starting materials, the following compounds are prepared: 5- chloro-1- [1- {3- [2,3-dihydro-3- (1-methylethenyl) - 2-oxo-1H-benz-imidazol-1-yl] -2-methylpropyl} -4-piperidinyl] -1,3-dihydro-2H-benz-imidazol-2-one as an oily residue, 6-chloro 1- {3- [4- (5-Chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl} -1,3-dihydro-2H-benzimidazole-2 -on, hydrate, m.p.

179.6 ° C, 1- {3- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl} -1,3-dihydro-5, 6 "dimethyl-2H-benzimidazol-2-one, 2-propanolate, m.p. 159 ° C, 6-chloro-1,3-dihydro-1- {3- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl} -2H -benzimidazol-2-one, m.p. 273 ° C, 1- {3- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl} -1,3-dihydro-2H-benzimidazole-2 -on, m.p. 225 ° C, 1,3-dihydro-1- {3- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl} -5 - (tri-methyl) -2H-benzyl-dazol-2-one, m.p.

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49 263.4 ° C, 5-Chloro-1- {3- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl} -1,3- dihydro-2H-benzimidazol-2-one, m.p. 253-255 ° C, 5-Chloro-1- [1- {3- [2,3-dihydro-2-oxo-3- (2-propenyl) -1H-benzimidazol-5-yl] propyl} -4 -piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one, m.p.

153.4 ° C, 1- {3- [3,6-dihydro-4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1- (2H) -pyridinyl] propyl} -1,3-dihydro-2H-benzimidazol-2-one, m.p. 206.6 ° C, 5-Chloro-1- [1- {3- [2,3-dihydro-3- (1-methylethenyl) -2-oxo-1H-benz-imidazol-1-yl] propyl} -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one, m.p. 165.2 ° C and 1- {1- [4- (1H-benzimidazol-1-yl) butyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one, m.p. 157.1 ° C.

Example 31

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 heated at reflux overnight under water discharge. 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 over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated to give 6 parts (67%) of 1- {3- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl ] propyl} -1,3-dihydro-5-methyl-3- (1-methylethenyl) -2H-benzimidazol-2-one as an oily residue.

Example 32 Following the procedure of Example 31 and using equivalent amounts of the appropriate starting materials, the following compounds are prepared: 1- {3- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazole) 1-yl) -1-piperidinylpropyl} -1,3-dihydro-5-methyl-3- (1-methylethenyl) -2H-benzimidazol-2-one as an oily residue, 3- {3- [ 4- (5-chloro-2,3-dihydro-2-oxo-lH-benzimidazol-l-yl) -L-

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Piperidinyl] propyl} -1,3-dihydro-5-methyl-1- (1-methylethenyl) -2H-benz-inridazol-2-one as an oily residue, 1- {1- [3- (1H-benzimidazole) -1-yl) propyl] -4-pipendinyl} -5-chloro-1,3-dihydro-2H-benzimidazol-2-one, m.p. 224 ° C and 5-chloro-1- {1- [3- (2-oxo-3 (2H) -benzoxazolyl) propyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one , m.p. 212.3 ° C.

Example 33

A mixture of 5.4 parts of 3- (3-bromopropyl) -2 (3H) -benzothiazolone, 4.5 parts of 5-chloro-1,3-dihydro-1- (4-piperidinyl) -2H-benzimidazole-2 -one, 5.3 parts sodium carbonate, 0.1 parts potassium iodide and 200 parts 4-methyl-2-pentanone are stirred and heated under reflux for 3 hours under water discharge. 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 off and dried to give 2.5 parts (31%) of 5-chloro-1,3-dihydro-1- {1- [3- (2-oxo-3 (2H) -benzothi azolyl] propyl] -4- piperidinyl} -2H-benzimidazol-2-one, mp 184.1 ° C.

Example 34

Following the procedure of Example 33, 1- {1- [3- (1H-benzo-triazol-1-yl) propyl] -4-piperidinyl} -5-chloro-1,3-dihydro-2H-benzimidazol-2-one , m.p. 203.4 ° by reacting 1- (3-bromopropyl) -1-benzotriazole with 5-chloro-1,3-dihydro-1- (4-piperidinyl) -2H-benzimidazol-2-one.

25

Example 35

A mixture of 5 parts of 1,3-dihydro-1- (3-iodopropyl-3-methyl-2H-benz-imidazol-2-one, 3.75 parts of 5-chloro-1,3-dihydro-1- (4) (piperidinyl) -2H-benz-imidazol-2-one, 2.65 parts sodium carbonate and 22.5 parts N, N-dimethylformamide are stirred at 70-80 ° C for 2 hours. The reaction mixture is cooled, poured into water and the precipitated product is filtered off. It is dissolved 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- (1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl) propyl] -35-4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one, mp 166, 5 ° C.

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51

Example 36

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 5 5, Ν-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 over silica gel using a mixture of trichloromethane and 10% methanol as eluent. The pure fractions are collected and the eluent is evaporated.

The crystalline residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized from a mixture of Ν, Ν-dimethylformamide and water. It is again filtered off and dissolved in a mixture of 4-methyl-2-pentanone and a small amount of Ν, Ν-dimethylformamide. The solution is filtered until clear and the filtrate is concentrated to a volume of about 15 parts. The concentrate is triturated in methanol. The precipitated product is filtered off and dried to give 1.27 parts of 5-chloro-1- (3- [4- (5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) -1) -piperidinyl] -propyl} -1,3-dihydro-2H-benzimidazol-2-one, mp 229-236 ° C.

Example 37

A mixture of 7 parts 1- (3-chloropropyl) -5-fluoro-1,3-dihydro- (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 part potassium iodide and 200 parts 4-methyl-2-pentanone are stirred and refluxed overnight over. The mixture is cooled to room temperature, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is stirred and heated under reflux overnight with a solution of 55 parts hydrochloric acid solution 6N in 40 parts ethanol. The solvent is evaporated and the residue is taken up in 30 water. The whole is made alkaline with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to the hydrochloride salt in 2-propanol. The salt is filtered off and dried to give 1.2 parts 1- {3- [4-

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52 (5-Chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl} propyl} -5-fluoro-1,3-dihydro-2H-benzimidazol-2-one, hydrochloride, hydrate, m.p.

250 ° C.

Example 38

Following the procedure of Example 37, 5-chloro-1- {1- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -butyl] -4-piperidinyl} -1,3- dihydro-2H-benzimidazol-2-one, hemihydrate, m.p. 258 ° C by reacting 1- (4-chlorobutyl-1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazol-2-one with 5-chloro-1,3-dihydro-1- (4) -piperidinyl) -2H-benzimidazol-2-one and 1- {1- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -4-piperidinyl} -1,3 -dihydro-3- (1-methylethyl) -2H-benzimidazol-2-one, m.p.

174.3 ° C by reacting 1- (3-chloropropyl) -1,3-dihydro-3- (1-methyl-ethenyl) -2H-benzimidazol-2-one with 1- (1-methylethyl) -3- (4-piperidinyl) -2H-benzimidazol-2-one.

Example 39

A mixture of 6 parts of 1- {3- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl} -1,3-dihydro-1 5-methyl-3- (1-methylethenyl) -2H-20 benzimidazol-2-one, 12 parts hydrochloric acid solution, 30 parts water and 40 parts ethanol are first stirred for a time at 50 ° C and further for 1 hour at room temperature. The reaction mixture is evaporated and the residue is crystallized from a mixture of 4-methyl-2-pentanone and 2-propanol.

The product is filtered off and dried to give 3.7 parts (40%) of 1- {3- [4-25 (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl} -1,3 dihydro-5-methyl-2H-benzimidazol-2-one, hydrochloride, hydrate, m.p.

251.4 ° C.

Example 40 Following the procedure of Example 39, the following compounds are recovered from the corresponding (1-methylethenyl) -substituted analogs: 5-chloro-1- {1- [3- (2,3-dihydro-5-methyl-2- oxo-1H-benzimidazol-1-yl) propyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one, hydrochloride, hydrate, m.p. 213.3 ° C, 5-chloro-1- {1- [3- (2,3-dihydro-6-methyl-2-oxo-1H-benzimidazole-1-

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S3 yl) propyl} -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one, hemihydrate, m.p. 195.4 ° C and 5-chloro-1- {1- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -2-methyl-propyl] -4-piperidinyl} - 1,3-dihydro-2H-benzimidazol-2-one, m.p. 244 ° C.

5

Example 41

A mixture of 38 parts of carbon disulfide, 6 parts of 1- [1- {3- [N- (2-amino-phenyl) amine] propyl} -4-piperidinyl] -5-chloro-1,3-dihydro-2H-benzimidazole - 2-ounce and 32 parts of ethanol are stirred and heated at reflux for 24 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-dimethyl formamide and water to give 3 parts (45.5%) of 5-chloro-1- {1- [3- (2,3-dihydro-2-thioxo) 1H-benzimidazol-1-yl) -propyl] -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one, m.p. 266.6 ° C.

15

Example 42

A mixture of 4 parts of 1- [1- {3- [N- (2-amino-5-chlorophenyl) amino] propyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one, 6 parts of concentrated hydrochloric acid solution and 30 parts of formic acid are stirred and heated to reflux overnight. The reaction mixture is evaporated and water is added to the residue. The whole is made alkaline with a dilute ammonium hydroxide solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized from 2-propanol to give 1.1 part (27%) of 1- {1- [3- (6-chloro-1H-benz-imidazol-1-yl) propyl] -4-piperidinyl } -1,3-dihydro-2H-benzimidazol-2-one, m.p. 214.9 ° C.

Example 43 A mixture of 20 parts of 1- [3- {4 - [(2-amino-4-chlorophenyl) amino] -1-piperidinyl] propyl] -1,3-dihydro-2H-benzimidazol-2-one , 52 parts of carbon dioxide sulphide and 120 parts of ethanol are stirred and heated under reflux for 24 hours. The reaction mixture is filtered after cooling and the filtrate is evaporated. The residue is crystallized from 2-propanol. The product 35 is filtered off and recrystallized from ethanol to give 7.5 parts (34%) of 1- {3- [4- (5-chloro-2,3-dihydro-2-thioxo-1H-benzimidazole)

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[1- (1-yl) -1-piperidinyl] propyl} -1,3-dihydro-2H-benzimidazol-2-one, m.p.

254.3 ° C.

Example 44 Following the procedure of Example 43, 1- {3- [4- (2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl} -1,3-dihydro-1 2H-benzimidazol-2-one, m.p. 248.5 ° C by reacting 1- [3- {4 - [(2-aminophenyl) amino] -1-piperidinyl} propyl] -1,3-dihydro-2H-benzimidazole-2-one with carbon disulfide.

10

Example 45

A mixture of 5 parts of 5-chloro-1- {1- [3- (2,3-dihydro-2-oxo-1H-benz-imidazol-1-yl) propyl] -4-piperidinyl} -1,3- dihydro-2H-benzimidazol-2-one, 10 parts acetic anhydride and 90 parts methyl benzene are stirred and heated under reflux overnight. The reaction mixture is cooled, water is added and the whole is made alkaline with a dilute sodium carbonate solution. The layers are separated and the organic phase is dried, filtered and evaporated. The residue is crystallized from methylbenzene. The product is filtered off and recrystallized from methylbenzene to give 4.5 parts of 3-acetyl-5-chloro-1- {1- [3- (3-acetyl-2,3-dihydro-2-oxo-1H-benzimidazole) -1-yl) -propyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one, m.p. 185.3 ° C.

Example 46 To a stirred solution of 1 part 5-chloro-1- {1- [3- (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) propyl] -4-piperidinyl} -1 3-Dihydro-2H-benz-imidazol-2-one in 32 parts ethanol is added a solution of 0.35 parts (±) tartaric acid in 8 parts ethanol. After stirring, the product is crystallized.

It is filtered off and dried to give 1 part (±) -5-chloro-1- {1- [3- [3- (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) propyl] -4- piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one, tartrate, ethanolate, m.p. 153.5 ° C.

Example 47

A stirred solution of 1 part 5-chloro-1- {1- [3- (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl] propyl] -4-piperidinyl} -1,3-dihydro-1 2H-benzimidazol-2-one in 20 parts of ethanol is saturated with gaseous hydrogen chloride.

DK 154950 B

55 hydrochloride salt is crystallized out with stirring. It is filtered off and dried to give 0.6 parts (53%) of 5-chloro-1- {1- [3- (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) propyl] -4 -piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one, hydrochloride, hydrate, m.p. 195.7 ° C.

5

Example 48

A solution of 1 part 5-chloro-1- {1- [3- (1,3-dihydro-2-oxo-2H-benz-imidazol-1-yl) propyl] -4-piperidinyl} -1,3- dihydro-2H-benzimidazol-2-one in 40 parts of ethanol is acidified with 2-propanol, which is previously saturated with 10 gaseous hydrogen chloride. Upon cooling, the hydrochloride salt formed is crystallized to give 1 part (83%) of 5-chloro-1- {1- [3- (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) propyl] -4 -piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one, hydrochloride, ethanolate, m.p. 213.7 ° C.

Example 49 10.2 parts 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 is converted to the 1 (+) tartrate salt in 100 parts of water at reflux temperature. The solution is treated for 10 minutes with a mixture of 0.5 parts activated 20 charcoal, 0.2 parts "Hyflo". The latter mixture is filtered off over "Hyflo" and the filtrate is cooled until an oily precipitate is formed.

The oily product solidifies upon heating for some time. The whole is left 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-1- {1- [3- (2,3-dihydro- 2-oxo-1H-benzimidazol-1-yl) propyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one, hemi- [R- (Rx, Rx)] ( +) - 1artrate, hydrate, m.p. 184.1 ° C, [<*] = + 5.13 ° (c = 1% CH 3 OH).

Example 50

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 1/2 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

DK 154950 B

56 evaporated. The solid residue is purified by column chromatography over silica gel using 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 to give 2 parts (24%) of 5-chloro-1- {3- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] propyl} 1 , 3-dihydro-2-benzimidazol-2-one, m.p.

190.8 ° C.

Example 51

A mixture of 3.58 parts of 1- (3-chloropropyl) -1,3-dihydro-5,6-dimethyl 2H-benzimidazol-2-one, 3.17 parts of 4- (4-chlorophenyl) -4-piperidinol, 5.3 parts of sodium carbonate, 0.2 parts of potassium iodide and 160 parts of 4-methyl-2-pentanone are stirred and heated under reflux for 24 hours under water-discharge. 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- (4-chlorophenyl) -4-hydroxyl-piperidinyl] propyl} -1,3-dihydro-5,6-dimethyl-2H-benzimidazole 2-one, hydrochloride, m.p. 260.8 ° C.

Example 52

A mixture of 2.3 parts of 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one, 2.12 parts of 4- (4-chlorophenyl) -4-piperidinol, 3.2 parts sodium 25 carbonate, 0.1 part potassium iodide and 80 parts 4-methyl-2-pentanone are stirred and heated under reflux for 36 hours. After cooling to room temperature, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and 10% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from methyl benzene to give 1 part (26%) of 1- {3- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] propyl} -1,3-dihydro-benzamide 2H-benzimidazol-2-one, m.p. 134.2 ° C.

Example 53

Following the procedure of Example 52 and using Equator 57

DK 154950 B

The following compounds are prepared from the appropriate starting materials: 6-chloro-1- {3- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] -propyl} -1,3-dihydro-2H- benzimidazol-2-one, m.p. 180.6 ° C, 1- [3- {4- [4-chloro-3- (trifluoromethyl) phenyl] -4-hydroxy-1-piperidinyl} propyl] -1,3-dihydro-2H benzimidazol-2-one, m.p. 189.2 ° C, 1- {3- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] propyl} -1,3-dihydro-3- (2-propenyl) -2H-benzimidazole-2 -on, m.p. 141.3 ° C, 1- {4- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] butyl} -1,3-dihydro-2H-benzimidazol-2-one, m.p. 160.6 ° C and 1- [3- (1H-benzimidazol-1-yl) propyl] -4- (4-chlorophenyl) -4-piperidinol, m.p. 160 ° C.

Example 54 A mixture of 5 parts of 1- (3-chloropropyl) -1,3-dihydro-3- (1-methyl-ethenyl) -2H-benzimidazol-2-one, 3.9 parts of 4- (4-fluorophenyl) ) -4-piperidinol, 5.3 parts sodium carbonate and 80 parts 4-methyl-2-pentanone are stirred and heated under reflux for 48 hours under water discharge. 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 and the organic phase is dried, filtered and evaporated.

The residue is purified by column chromatography over sieve in cage! using a mixture of trichloromethane and 10% methanol as eluant. The pure fractions are collected and the eluent is evaporated. The oily residue is dissolved in 2-propanone. The solution is acidified with 2-propanol, which is pre-saturated with gaseous hydrogen chloride, and the whole is stirred and heated under reflux for 15 minutes. The solvent is evaporated and the hydrochloride salt formed is dissolved in water. The free base is conventionally released with a dilute sodium hydroxide solution. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is crystallized from methyl benzene. The product is filtered off and dried to give 2.5 parts of 1- {3- [4- (4-fluorophenyl) -4-hydroxy-1-piperidinyl] propyl} -1,3-dihydro-2H-benzimidazole-2 on, m.p.

135.4 ° C.

35

Claims (3)

1, Anal and in Process for Preparation of 1- (Benzazolylalkyl) -piperidine Derivatives of the General Formula 5 3 R Bv 'y- (CH2> n.- ™ - (CH2) n-N A> <H> · · w (I) 10 R 2 or pharmaceutically acceptable acid addition salts thereof, wherein 1 2 15. and R are each independently a group or atom in the form of hydrogen, halogen, C 1-6 alkyl or trifluoromethyl, B is a bivalent group in the form of 0 O is -N (L) -C1-, -SC-, -O-C-, -N = N- or -N = CH-, where L is a group or atom in the form of hydrogen, C1-5 alkyl , Cj_g alkyl carbonyl or C₂_g alkenyl, and wherein the bivalent groups are bonded to the benzene nucleus via their heteroatoms, R3 is a group or atom in the form of hydrogen or methyl, m and n are each an integer of 1 or 2, and The group is 30 a) a group of the general formula. Wherein: the group is 30 a) a group of the general formula. R 4 is a group or atom in the form of hydrogen or C 1-4 alkyl and R and R 6 are each independently a group or atom in the form of hydrogen, halogen, C 15 alkyl or trifluoromethyl, b) a group having the general formula Y -n4i4n-M 20. S8 'wherein 7 8 R and R are each independently a group or atom in the form of hydrogen, halogen, C1-5 alkyl or trifluoromethyl, Y is an atom in the form of 0 or S, M is a group or an atom in the form of hydrogen, C 1-6 alkyl or C 15 alkylcarbonyl, and the dotted line means that the bond between the carbon atoms 3 and 4 in the piperidine nucleus is optionally a double bond, provided that when Y is S there is a single bond between the carbon atoms 3 and 4 in the piperidine nucleus, in which case 30 M is hydrogen, or c) a group of the general formula 35 wherein g 10. is a group or atom in the form of hydrogen, halogen, C, r-. all alkyl 10 1-5 or trifluoromethyl, and R is an atom in the form of hydrogen or halogen, characterized in that a) reacting a compound having the general formula 15 N- (CH 2) m - CH- (CH2) nX Q R 12, R 2 wherein 12 3 R, R, R, m, n and B are as defined above and X is a suitable reactive ester functional group derived from the corresponding alcohol having a compound having the general (III) 30 wherein A is as defined above in a suitable organic solvent, or b) in a manner known per se, removes the protecting group P from a compound having the general formula DK 154950 BO R3 5 pA (-lCH2) m ^ H "(CH2) '' 'N'J' (W) r1 RZ 10 wherein 12 3 R, R, R, m, n and A have the meaning given above, for preparation of a compound having the general formula ° (3) 11 * H v!? '(CH2) m'CH' (CH2) n'NwA Q R1 R2 20 or c) subject to a compound known per se , which has the general formula 25 R3 '· I \ A! Wherein Q 3 R, R, R, m, n and A have the meaning given above, DK 154950 B ring closure with a suitable ring closure means for preparing a compound having the general formula R3 5 Ό! (ic) R1 R210 wherein B2 is -NH-C (O) - or -N = CH-, or d) in a manner known per se, terminates a compound having the general formula r3 - (CH,) -CH- (CH) -NV 20 v 27m Z n \ _ / NH NH2 RI_ R2 ^ 8 R * R 25 wherein R1, R2, R3, R7, R8, m, n and B have the meaning given above using suitable cyclization agents, for the preparation of a compound having the general formula 30 R 3 R 2 R 7 R 7 R 7! DK 154950B wherein Y is S or O, or e) in a manner known per se, produces a compound having the general formula "f" - \ - OB / "~ N- (CH2) in" CH- ( CHE) n '\ _ 10. ifi · u "fl R1 R2 R7 R8 15 wherein R1, R ^, R' *, R ^ R®, m, n and B have the meaning given above and wherein M1 is C -alkyl or C 15 -alkyl carbonyl, by N-alkylation or N-acylation, respectively, of the corresponding unsubstituted compound with appropriate alkylating or acylating agents, in the case where B in the compound (If) is -NH-C ( O) -, preferably as starting material, uses a compound of the general formula Π Ϋ \ HO R12.CH = cN; ^ N- (CH2) m-CH- (CH2) nN V in hl V— / N— 'Nv /, (IV-a): · Q, Q R1 R 7 ^ 8: R R 30 which is then N-alkylated or N-acylated, after which the protective substituted ethenyl group is eliminated by acid hydrolysis in known manner, wherein R in the protecting group is C 1-6 alkyl and R is hydrogen, Cj_g alkyl or phenyl, in which one step can be subjected to the compound of formula (If) wherein B is N (L) -C (O) - wherein L is a Cj ^ - DK 154950 B alkyl or a Cjj -alkylcarbonyl group identical to M *, an alkylation or acylation of both 1H-benzimidazole groups therein, or, if desired, to produce pharmaceutically acceptable acid addition salts of the products of steps (Ia) to (Ie). A process according to claim 1 for the preparation of 5-chloro-1- {1- [3- (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) propyl] -4-piperidinyl} -1, 3-dihydro-2H-benzimidazol-2-one or the pharmaceutically acceptable acid addition salts thereof, FEATURED by reacting 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one with 5-chloro-1, 3-dihydro-1- (4--10 piperidinyl) -2H-benzimidazol-2-one and, if desired, produce a pharmaceutically acceptable acid addition salt of the resulting product. The process of claim 1 for the preparation of 8- [3- (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) propyl] -1- (4-fluorophenyl) -1,3,8 triazaspiro [4,5] decan-4-one or pharmaceutically acceptable acid addition salts thereof, FEATURED by reacting 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one with 1- ( p-fluorophenyl) -1,3,8-triaza-spiro [4,5] decan-4-one and, if desired, produces a pharmaceutically acceptable acid addition salt of the resulting product. 20 25 30 35