DK153477B - METHOD OF ANALOGUE FOR THE PREPARATION OF 1-SUBSTITUTED 4- (DIARYLMETHYL) PIPERAZINE OR 1-SUBSTITUTED 4- (DIARYLMETHOXY) PIPERIDE INGREDIENTS OR PHARMACEUTICAL ACCEPTABLE ACID ADDITIONABLE ACID ADDITIONAL ADDITION - Google Patents

Description

in

DK 153477B

The present invention relates to an analogous process for the preparation of novel 1-substituted 4- (diarylmethyl) piperazine or 4- (diarylmethoxy) piperidine derivatives having anti-anaphylactic and anti-histamine-acting properties. The process is peculiar to the characterizing part of claim 1.

A number of 1 - [(heterocyclyl) alkyl] piperazines and a number of 1-substituted 4- (diarylmethyl) piperazine and 4- (diarylmethoxy) piperidine derivatives are known which have pharmacological properties. Such compounds are described in the following references: U.S. Patent No. 3,362,956, U.S. Patent No. 3,472,854, U.S. Patent No. 3,369,022, U.S. Patent No. 2,882,271, U.S. Patent No. 3,956,328, and CA, 64, 3499e (1966).

The compounds of this invention differ substantially from the foregoing by the nature of the B-CnH2n group present in the 1-position of the piperazine or piperidine group and / or by the nature of the diarylmethyl or diarylmethoxy group present in the 4 position in this piperazine or piperidine group, respectively.

By analogous process according to the invention, the above-mentioned novel piperazine or piperidine derivatives of the general formula are prepared:

2 DK 155477 B

1 2

Ar and Ar are each a group in the form of phenyl, substituted phenyl or pyridinyl, wherein in the substituted phenyl is phenyl with from 1 to 2 substituents, each of which is in the form of halo C 1-6 alkyl, C ^gg alkyloxy, trifluoromethyl or nitro, m is the integer 0 or 1, A is a group in the form of or "CHCH CH, provided that m-is 0 when A is ^ N N -, and m is 1, hair A is ^ CH -, n is an integer of 2 to 6 inclusive, provided that at least 2 carbon atoms are present in the linear portion of the chain connecting B to the piperidine or piperazine nitrogen network. when cnH2n represents a branched alkylene chain and B is a group in the form of: a) a group of the general formula:

ISLAND

R1 and R2 are each an atom or a group in the form of hydrogen, halogen, C1-4 alkyl or trifluoromethyl, and Y is an atom or group in the form of oxygen, sulfur or a substituted nitrogen wherein: L is an atom or group in the form of hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl-C 1-6 alkyl, carboxy-C 1-6 alkyl, phenyl, phenylmethyl, C alkylamino carbonyl, hydroxymethyl or C 1-6 galkenyl, provided that when Y is oxygen or sulfur, R 1 and R 2 are both hydrogen, Ar and Ar are both phenyl, A is N and n is 3, or

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(B) a group of the general formula:

M

Wherein R and R are individually an atom or a group in the form of hydrogen, halogen, C1-6 alkyl, or trifluoromethyl, and M is an atom or group in the form of hydrogen, C1-6g. alkyl, phenyl, phenylmethyl, mercapto, C 1-6 alkylthio, amino, C 1-6 alkylcarbonylamino, C 1-6 alkyloxycarbonylamino or cycloalkyl having from 3 to 6 carbon atoms, provided that M is other than hydrogen or C 1-6 alkyl when> A-

The compounds of the process of the present invention have an activity which is surprisingly higher than that of closely related compounds known from the above-mentioned United States Patent No. 3,362,956. This is shown by comparing the results of known compounds in Tables (1-f) with the results of Tables (1-a) to (1-e) of compounds of the present invention.

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4 In the foregoing and in the following definitions, "lower alkyl" shall comprise straight-chain and branched hydrocarbon radicals having from 1 to 6 carbon atoms, such as e.g. methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl or hexyl; "lower alkenyl" shall comprise straight-chain and branched alkenyl radicals having from 2 to 6 carbon atoms, such as e.g. ethenyl, 1-methylethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 1- methyl-2-butenyl, 2-pentenyl or 2-hexenyl; "cycloalkyl" means cyclic hydrocarbon radicals having from 3 to 6 carbon atoms, such as e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; the term "cnH2n" means straight-chain and branched-chain alkylene chains having from 2 to 6 carbon atoms and with at least 2 carbon atoms in the linear portion of the chain connecting the B group to the piperidine or piperazine nitrogen, e.g. 1,2-ethanediyl, 1,3-propanediyl, 2-methyl-1,3-propanediyl, 1,4-butanediyl, 2-methyl-1,4-butanediyl, 1,5-pentanediyl or 1 hexanediyl; and the term "halogen" is common to atomic halogens less than 127, i.e. fluorine, chlorine, bromine and iodine.

The present compounds of formula (I), other than those in which B represents a 2-amino-1H-benzimidazol-1-yl radical, can be conveniently prepared by a process which is characterized by reacting an appropriate reactive ester , which has the general formula (II) wherein n has the previously stated meaning, B has the previously stated meaning, except for a 2-amino-1H-benzimidazol-1-yl radical, which has the general formula: HH2 g .

E1 B2 2 2 wherein R and R have the meanings previously stated,

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5 and W are an appropriate reactive ester function / derived from the corresponding alcohol, such as e.g. halogen, methanesulfonyl or 4-methylbenzenesulfonyl, with a suitable piperidine or piperazine derivative having the general formula (III) wherein A, m, Ar and Ar have the meanings previously stated: / - H0 -W + HN A- (0) -CH (I) 11 2n W m \ Ar2 -> (II) (III)

The above condensation reaction is preferably carried out in a suitable reaction inert organic solvent, such as e.g. a lower alkanol, e.g. methanol, ethanol, propanol or butanol; an aromatic hydrocarbon, e.g. benzene, methylbenzene or dimethylbenzene; an ether, e.g.

1,4-dioxane or 1,1'-oxybispropane; a ketone, e.g. 4-methyl-2-pentanone; Ν, Ν-dimethylformamide; or nitrobenzene. Addition of a suitable base such as e.g. an alkali metal or iodine alkali 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 promoter. Slightly elevated temperatures are suitable for increasing 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 reaction mixture and further purified, if necessary, by the practice of a method well known in the art.

The compounds having formula (I) wherein B is a 2-amino-1H-benzimidazol-1-yl radical, (I-a) are readily prepared

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6 from the corresponding compounds (I) wherein B is a 2- (lower alkyloxycarbonylaird.no) -1H-benzimidazol-1-yl radical, (Ib), by a process which is characterized by decarboxylating it last listed radical under hydrolytic conditions, e.g. by acid hydrolysis using a suitably strong acid such as hydrochloric, hydrobromic or sulfuric acid, or by alkaline hydrolysis using a suitably strong base such as e.g. sodium or potassium hydroxide.

^ ίΗ-COQ (lower alkyl) H + or OH ~ _ \ _ / n 2n \ _ / K \ o -—-> E1 E2 (xb) / -v fC> "CAa'trWA- (°) n.-C 'C -

ISLAND

R 2 da) When the B group in the compounds of formula (I) or in intermediates therefore means a 2- (lower alkyloxycarbonylamino) -1H-benzimidazol-1-yl or a 2- (lower alkylcarbonylamino) -1H -benzimidazol-1-yl radical, it should be noted that these radicals may exist in various tautomeric forms as illustrated below: NH-COO (lower alkyl) N-COO (lower alkyl) a '- * tt a K E1 E2 7

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NH-CQ- (lower alkyl) N-CO- (Lower alkyl) 1Ι ^ Ίί_ HT'® '' - y {* - ^ ri E ^ R2 E1 E2 Such tautomeric forms of compounds of formula (I) should of course be considered for being within the scope of the invention.

Compounds of formula (I), which may be represented by formula (Ic): γ y ~ \ f \ ** E1 E2 (Ic) 12 12 wherein R, R, η, A, m, Ar and Ar have the meanings previously stated. alternatively, can be prepared by a process which is characterized by cyclizing an appropriate intermediate having the general formula (IV) with an appropriate cyclizing agent, as is well known in the art of preparing 1,3-dihydrohydrocarbons. 2H-benzimidazole-2-ones from 1,2-benzene diamines.

Suitable ring closure agents which may advantageously be used include, for example, urea, carbonyl dichloride and alkali metal isocyanates, and the cyclization reaction can be carried out according to the method well known in the art.

Eg. For example, compounds (I-c) are readily obtained by stirring and heating the reactants together in the absence of any solvent when urea is used as a cyclizing agent.

The above procedure can be illustrated as follows:

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8 / - \

H 2 N r 2 -C 2 -N 2 A-CO 2 -CH

Ά R1 R ^ (IV) ring slope _ (I-c) means

Furthermore, the compounds of formula (I-c) can be prepared from the corresponding compounds having the general formula (V) in P

- P-0'C "H2n - '\> CO)« - OT

A Ar R1 R ~ (V) 12 12 wherein R, R, η, A, m, Ar and Ar have the meanings previously stated, and P is an appropriate protecting group, by a method peculiar to the removal of the protecting group in accordance with conventional methods. Examples of such protecting groups include lower alkyloxycarbonyl and a substituted ethenyl group having the general formula: 4 R -CH = C- '3

R

Wherein R is lower alkyl and R is hydrogen, lower alkyl or phenyl.

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When the protecting group is lower alkyloxycarbonyl, it can be easily removed by alkaline hydrolysis and when the protecting group is a substituted ethenyl group, it is conveniently cleaved by exposing the appropriate intermediate (V) to acidic hydrolysis. In carrying out the acidic hydrolysis to remove the substituted ethenyl group from (V), a large amount of various protonic acids, including mineral acids such as e.g. salt, hydrogen bromide, sulfur, nitric or phosphoric acid, and organic acids, such as e.g. acetic, propionic or oxalic acid. Furthermore, the reaction may be carried out in reaction-inert solvents which are usually used in such a type of hydrolytic reaction, e.g. lower alkanols such as methanol, ethanol or 2-propanol.

By a method similar to that described for the preparation of the compounds (Ic) from (IV), compounds having the general formula (Id) may also be prepared: M1 1 1 j-y .. Ar XAr 2 dd) E1 S2 12 Wherein R, R, η, A, m, Ar and Ar have the meanings previously set forth and LF is an atom or a group in the form of hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, amino, lower alkyloxycarbonylamino or cycloalkyl .

by reacting (IV) with a suitable cyclization agent according to the method well known in the art for the preparation of 1H-benzimidazoles from 1,2-benzene diamines. For example, depending on the nature of M1 in the compounds (I-d), the cyclization agents listed below may be used.

When hydrogen means, formic acid or one can be used

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suitable tri (alkyloxy) methane as a cyclization agent.

When lower alkyl, phenyl, phenylmethyl or cycloalkyl / a carboxylic acid having the general formula R5-COOH (VI) 5 wherein R is lower alkyl, phenyl, phenylmethyl or cycloalkyl, or a functional derivative thereof, eg. acyl halide, ester, amide or nitrile derived from such acids, or an imino ester having the general formula: O- (lower alkyl) HN = C (VII) X5 wherein R is as defined above; or an aldehyde having the general formula:

yo

R5-C2 (VIII) \ h or an addition product thereof with an alkali metal hydrogen sulfite. When the cyclization agent is an aldehyde, a suitable oxidizing agent, such as e.g. nitrobenzene, mercuric oxide, Cu (II) or Pb (II) salts or other well-known oxidants known in the art, or the aldehyde itself can, by addition in excess, serve as an oxidant.

When M ^ means mercapto, cyclization agents such as e.g. carbon disulfide, thiourea, thiocarbonyl chloride or ammonium thiocyanate.

When an amino group, cyclization can be carried out with cyanamide or a metal salt thereof, preferably an alkali or alkaline earth metal salt, or with BrCN.

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For example, when M

NH O

It II

H 1 -C-O-C-NH-O-O (lower alkyl) (IX) g or a lower alkyl [(lower alkoxycarbonylamino) (R-thio) methylene] carbamate having the general formula (X):

O S O

II V II

(lower alkyl) -O-C-N-C = N-C-O- (lower alkyl) (X) g wherein R is hydrogen or methyl, or a lower alkyl carbonoisothiocyanatidate having the general formula (XI)

ISLAND

(lower alkyl) -O-C-NCS (XI) or a lower alkyl-lower alkylcarbamothioate having the general formula (XII)

S

II

(lower alkyl) -NH-C-O- (lower alkyl) (XII) or a diluted alkyl cyanimidodicarbonate having the general formula (XIII)

ISLAND

[(lower alkyl) -O-C] 2N-CN (XIII)

The above cycle closure reactions can all be performed according to well known methodology as described in the literature.

Compounds having the general formula (I-e): 12

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NH-CQ- (lower alkyl) -1 L-CH, -N A- (O) -CH. .

\ _ / n 2n \ _ (m \ Λ 2 (I "e)

M

R1, R12, 12, wherein R, R, n, A, m, Ar and Ar have the meanings previously set forth, may alternatively be prepared by a process which is peculiar to acylation of an appropriate 2-amino-1H-benzimide- azol-1-yl derivative having the formula (Ia) in accordance with standard N-acylation processes, e.g. by the reaction of (I-a) with a suitably lower alkylcarbonyl halide or with an anhydride derived from a lower alkylcarboxylic acid.

Compounds having the general formula (I-f): 8 Ar1 ΐ'-Λ-ί Η, - / V- (0) -cif

W n 20 W m \ a a, T

Ar df) S1 R2 12 12 wherein R, R, η, A, m, Ar and Ar have the meanings previously set forth and are a group in the form of lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl-lower alkyl, carboxy-lower alkyl , phenylmethyl, lower alkylaminocarbonyl, hydroxymethyl or lower alkenyl, on the condition that this lower alkenyl is unsaturated at a position different from the α-position, can further be prepared by a method which is characterized by introducing ΐΛ in a compound having formula (Ic): 13

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o, 1

"/ -V

\ _ / · (0) »· ^ 2 Q <i" °)

1 2 E R

Depending on the nature of the L + group to be introduced, the following methods can be used for this.

When L1 means lower alkyl, lower alkyloxycarbonyl- lower alkyl, phenylmethyl or lower alkenyl, in which case the symbol is used, the introduction of 1a L into (Ic) can be carried out by reacting (Ic) with an appropriate α 11 reactive ester which has the formula L -W, (XIV), wherein L has 3. α has the meaning given above and W has the same meaning as stated in the definition of the starting materials of formula (II). The condensation of (XIV) with (I-c) can be carried out under similar conditions as described herein before for the condensation of the reactive esters (II) with the intermediates having formula (III). To increase the reaction rate, it may in some cases be appropriate for the reaction mixture to add a small amount of a suitable macrocyclic polyether such as e.g. 2,3,11,12-dibenzo -1,4,7,10,13,16-hexaoxacyclooctadeca-2,11-diene as a promoter of turnover.

Alternatively, when the L ind group to be introduced is lower alkyloxy-carbonylethyl, the introduction of this group may be carried out by reacting (Ic) with a (lower alkyl) -2-propenoate having the general formula (XV) (lower). alkyl) OOC-CH = CH2 (XV)

This reaction can conveniently be carried out in a reaction-inert organic solvent such as e.g. an aromatic hydrocarbon, e.g. benzene, methylbenzene or dimethylbenzene; an ether, e.g. 1,1'-oxybisethane, 2,2'-oxybispropane, tetra-14

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hydrofuran or 1,4-dioxane, preferably in the presence of a suitable aluminum hydroxide, such as e.g. Ν, Ν, Ν-triethylbenzene-methanaminiumhydroxid.

Compounds of formula (I-f) wherein L1 is carboxy lower alkyl can be readily derived from the corresponding lower alkyl-. oxycarbonyl-lower alkyl-substituted compounds by hydrolysis thereof in the usual manner, for example, with aqueous alkali, to release the acid from the ester.

When the L ^ group is lower alkylcarbonyl, this group can be conveniently introduced by reacting (I-c) with an appropriate acylating agent derived from the corresponding lower alkylocarboxylic acid, such as e.g. a halide, preferably the chloride, or an anhydride, in accordance with standard N-acyl ring procedures.

When lower alkylaminocarbonyl means, the group may be introduced by reacting (I-c) with a suitable isocyanatoalkane in a suitable reaction inert organic solvent, such as e.g. an ether, e.g. 1,1'-oxybisethane, 2,2'-oxybispropane or 1,4-dioxane.

When ΐΛ is a hydroxymethyl group, its introduction can be conveniently carried out by reacting (I-c) with formaldehyde in a suitable organic solvent, such as e.g. N, N-dimethyl-formamide.

Compounds having the general formula (I-g): ΑΓ1 / - ^ k

B-C H ~ -N N-CH

n-n \ / \ 2

Ar (I-g) 2 wherein B, n, Ar and Ar have the meanings previously stated,

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Alternatively, 15 can be prepared by a process characterized by condensing a piperazine derivative having the general formula (XVI) with a suitable reactive ester having the general formula (XVII) wherein Ar, Ar and W have the meanings previously stated, under conditions similar to those previously described for the preparation of compounds (I) from (II) and (III).

WJ + W-C ^ (> I-ff) (XVI) (XVII)

A number of the intermediates of formula (II) are well known compounds, some of which are disclosed in U.S. Patent Application No. 597,793, filed July 21, 1975, and in U.S. Patent Application No. 620,727, filed October 8, 1975, and all of them may be disclosed. are prepared according to methods well known in the art. Depending on the nature of B in the intermediates (II), the following methods of preparation can be used to prepare them.

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Intermediates having the general formula (II-a) 0 µ ™ ry-cnK2n-v / r \ (Il-a) r 'r2 can be prepared as follows:

An appropriately substituted 2-chloro nitrobenzene having the general formula (XVIII) is reacted with an appropriate aminoalkanol (XIX) by heating the reactants together under reflux in a suitable reaction inert organic solvent, such as a lower alkanol, e.g. ethanol, propanol, 2-propanol or butanol to give a [(2-nitrophenyl) amino] alkanol having the general formula (XX), which is again subjected to a nitro-to-amine reduction, e.g. by catalytic hydrogenation using Raney nickel catalyst. The intermediate (XXI) thus obtained is then reacted with a suitable cyclization agent as hereinbefore described for the preparation of the compounds (Ic) from (IV), and the alcohol thus obtained having the general formula (XXII) is then converted to the desired reactive ester (II-a) by the practice of methods well known in the art. Halides are conveniently prepared by reacting (XXII) with a suitable halogenating agent such as e.g. sulfinyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus pentabromide or phosphoryl chloride.

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

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The above reactions are more clearly illustrated by the following scheme: o2n Cl W + H2H-CnH2a-0H - * S1 “e2 (XIX) (XVIII)

02N r o -C ^ H ^ -OH

\ - (H0 / RaNi f \ 2-> R1 a2 (XX) ¥ wæW! F, A ring ending O -> R1 R2 (XXI) o

X

reactive ester- (R) (II-a) y X Formation R1 R2 (XXII) 18

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Alternatively, the intermediates of formula (II-a) may also be prepared by: i) reacting a compound having the general formula 34 (XXIII) wherein R and R have the previously mentioned meanings with a haloalkanol having the general formula (XXIV), by conventional N-alkylation processes to obtain an alcohol having the general formula (XXV); ii) converting the hydroxyl function of (XXV) to a reactive ester group in the usual manner as previously described; and iii) decomposes the substituted ethenyl group into the compound thus obtained (XXVI) by acid hydrolysis as hereinbefore described to prepare (I-c) from (V).

The introduction of the hydroxyalkyl chain into (XXIII) to give (XXIV) can also be carried out by reacting (XXIII) with a suitable 2- (haloalkyloxy) tetrahydro-2H-pyran having the general formula (XXVII) to give an intermediate , which has the general formula (XXVIII), whose ether function is hydrolytically cleaved, e.g. by treatment with an aqueous hydrochloric acid solution.

Alternatively, when the reactive ester (II-a) is a halide, (II-a-1), it can be prepared by reacting (XXIII) with an equivalent amount of a suitable dihaloalkane, (XXIX), in the presence of a suitably strong base, such as sodium methoxide, or in accordance with a Mackosza process using aqueous alkali and a quaternary ammonium catalyst, e.g. Ν, Ν, Ν-triethylbenzene methanaminium chloride to give an intermediate having formula (XXVI-a), the substituted ethenyl group being then removed by acid hydrolysis to give the desired halide (II-a-1).

It should be noted that the same methods are also applicable when the substituted ethenyl group is replaced by another suitable protecting group except that removal 19

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thereof shall be carried out in accordance with appropriate methods for cleavage of the particular group involved.

The previous turnovers are more clearly illustrated by the following table:

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ti 0 tn S «

5 S

1 o V

g ^ H ei

CM X «3 O

• X Η Λ H

S5 X I 2 0 x s λ Λ 1 w CM I ^

ti X S ΤΟ) g * -N CM- I

&> o <d x <ø

O in CM 1 + ti I

H 04 Η X O H

«/ ^ Y \\ ί»> i cm h λ a yt ^ / i-3 </ 11 s / Mm / o / 1 / <f / w Φ ° p * g o ^

CM ^ I H

X H · ti W

to Hi CM H

O> X> cm r x s y

“Η I S i C« S

./ri si. jw S s ^ «

I cn. j t n I

0—04 O — 04 H

«Jl · w.

X X w

Island Island

Bi «

\ <D

ω

H

0 0! + + ti x X ø -3

U

O Ύ <u

I + J

g - «- s x cn cm> o <u> X H I. in g> <s> s

o> 4 cm CM

1 w X 4J x fi s% ti 0 o ø o

Cn I CM ^ I CM ^ S / * S ^ “ΛΑ * g g / siA« X Χ ^ </ ^ 04 w i co X I co 0—04 '0—04 I! li * -M> r *

MM MM

ISLAND ISLAND

i

ISLAND"

X X

21

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Intermediates having the general formula (II-b) 0 µl (II-b)

R1 R

1 2 wherein R, R, n and W have the meanings previously stated and 2 L is a group in the form of lower alkyl, lower alkenyl, lower alkyloxycarbonyl-lower alkyl, phenyl, phenylmethyl or lower alkylaminocarbonyl, can be conveniently prepared by introducing the reactive ester side chain in an starting compound having the general formula (XXX).

Pi

L2 NX) ^ H

) Xx \ (xxx) R 2 R2 in accordance with procedures similar to those described herein for the preparation of the intermediates (XXVI) from (XXIII).

Intermediates having the general formula (II-c) 0

H0CK2-N ^ y-C n H 2n-W

Y Y di-ο r 'r 2 can be prepared from the corresponding (II-a) compound at 22

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hydroxymethylation thereof in the usual manner with formaldehyde. Intermediates having the general formula (II-d)

M

(n-d) R1 R2 except those in which M represents a mercapto or lower alkyl thio group is conveniently obtained by introducing the reactive ester seat chain into an starting compound having the general formula (XXXI)

M

y_ / (xxxi)

The introduction of the cnH2n-W group can be carried out in accordance with similar procedures to those described herein for introducing this group into starting compounds of formula (XXIII).

Intermediates having the general formula (II-e) M1 (II-e) R1 R2 12 1 wherein R, R, M, nogW have the meanings previously stated, 23

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can be prepared by subjecting a suitable alcohol of formula (XXI) to cyclization with a suitable cyclizing agent / as previously described, and then converting the hydroxyl group of the intermediate thus obtained having the general formula (XXIII) to a reactive one. ester group.

(F) (χχΐ) cyclization of reactive ester, (II-e)

The intermediates having the general formula (II-f) S - (lower alkyl) ir r 2 are conveniently obtained by S-alkylation of a suitable intermediate having the general formula (XXXII) wherein M ^ is mercapto, (XXXII-a) in accordance with standard S-alkylation methods, e.g. with an appropriate halogenated alkane and subsequent conversion of the hydroxyl function of the thus obtained compound (XXXIII) to a reactive ester group.

24

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p * S-cavity alkyl)

0 ^ Η ^ - ° Η S ^ ylertag fHV

Q ——> <H> R1 R2 O 2 R1 R2 (XXXII-a) (XXXIII) Reactive Ester Formation ^

Intermediates having the general formula (II-g) NH-CO- (lower alkyl)

N ^ N-C H0 -W

W (II-g) R1 R2 is conveniently prepared by N-acylation of the corresponding amino-substituted analog compound, (II-h) tr 2 ways, e.g. by reacting (II-h) with a suitable lower 25

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alkylcarbonyl halide or with an anhydride derived from a suitably lower alkyl carboxylic acid.

The intermediates having formula (IV) are obtained by condensing a suitable reactive ester having the general formula (XXXIV) with a piperazine or piperidine derivative having the general formula (III) followed by reduction of the nitro group in the intermediate (XXXV) thus obtained to an amino group in accordance with standard nitro-to-amine reduction methods, e.g. by reacting the nitro compound with nascent hydrogen or by catalytic hydrogenation in the presence of a suitable catalyst such as e.g. Raney nickel.

ΟΛ, ΝΗ - ^ - »Q + (in) ->

1 'O.

R 2 (XXXIV)

Ar1 / - \ /

0Nx NH-C H0 -N A- (O) -CH

2 \ - / a2a \ o fl \ Ar U \> mtro = * to-amine- y / -v, (IV) '' reduction R1 R2 (XXXV)

The reactive esters having the general formula (XXXIV) and used herein as starting compounds can be readily prepared from an alcohol of formula (XX) by converting the hydroxyl function thereof into a reactive ester group according to standard procedures as hereinbefore described. described.

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The intermediates having the general formula (V) can be obtained by condensing a reactive ester of formula (XXXIV) with a piperazine or piperidine derivative having formula (III) 0

U

P-N ^ h-C H «-V r \ 7 n 2n + (111) _ ^ (v) E1 £ 2 (XXXVI)

The reactive ester (XXXIV) used herein as a starting compound can further be prepared by introducing the cnH2nW_ group into an starting compound having the general formula (XXXVII) 0

II

(/ \ (XXXVII) E1 E2 in accordance with methods previously described herein).

The intermediates having the general formula (XVI) can be prepared by reacting a reactive ester having the formula (II) with a piperazine derivative having the general formula 2 (XXXVIII) wherein Q is an appropriate protecting group , such as. phenylmethyl or lower alkyloxycarbonyl, and subsequently removing the protecting group Q from the intermediate thus obtained (XXXIX) in accordance with standard methods well known in the art, e.g. by catalytic hydrogenation using palladium-on-charcoal catalyst when Q means phenylmethyl, or by alkaline hydrolysis when Q means lower alkyloxycarbonyl.

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27 (II) - ΗΝ ^ Λ-q - (xxxvin) '(xxxix) removal of Q (XVI)

Intermediates having the general formula (XVI-a) 0 (xvi-a) may alternatively be prepared by reacting (XXXVI) with (XXXVIII) to obtain an intermediate having the general formula (XL) and subsequently removing the protecting groups P and Q by conventional methods well known in the art.

0 (xxxvi) + (XXXVIII). p-tr ^ Kr-c h „-t / -Vo —7 \ _ / a \ /

Q

B1 B2 (XL) fi / - \ removal of ΗΚ ^^ - 0_Η -W Yo - \ / n 2n \ y

P VV

R1 x R2 (XXXIX-a) removal of (XVI-a)

Q

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Intermediates having the general formula (III) wherein A is and m is 0, (III-a) are generally well known and can all be prepared by the practice of methodology well known in the art. Such intermediates (III-a) can e.g. is prepared by first exposing a suitable aryl halide to a Friedel-Craft reaction with a suitable scaffold to obtain an Ar, Ar-methanone, which is again reduced in the usual manner, e.g. with sodium borohydride, to the corresponding methanol derivative. This last compound is then converted to a reactive ester (XVII) in accordance with standard processes for producing reactive esters from alcohols, and the desired intermediates (III-a) are then obtained by reacting (XVII) with piperazine.

The intermediates having the general formula (III) wherein \ A is CH- and m is 1 (III-b) can be conveniently prepared by O-alkylation of a 4-piperidinol having the general formula (XLI), wherein Q is an appropriate protecting group as previously defined, with an appropriate reactive ester having formula (XVII) followed by removal of the protecting group from the compound thus obtained (XLII) in the usual manner.

/ “Λ h / - \

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δ * "ap2 (III-b)

DK 153477B

29

The original starting materials used in all the foregoing methods are usually well known and can all be prepared according to methods well known to those skilled in the art.

The compounds of formula (I) can be converted to the therapeutically active non-toxic acid addition salt form by treatment with a suitable acid, such as e.g. an inorganic acid such as hydrogen halide acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric or phosphoric acids; or an organic acid such as e.g. vinegar, propion, glycol, milk, pyruvate, malon, amber, fumar, male, apple, wine, lemon, benzo, cinnamon, almond, methanesulfone, ethanesulfone , benzene sulfone, 4-methylbenzenesulfone, cyclohexane sulfamine, salicylic or p-aminosalicylic acid Conversely, the salt form can be converted by treatment with alkali to the free base form.

The present compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof possess strong anti-anaphylactic and anti-histamine-acting properties and as such are useful agents for human and animal therapy. The useful anti-anaphylactic and antihistamine-acting properties of the compounds of this invention are clearly demonstrated by the results obtained by the test methods described below.

It should be emphasized that the compounds listed in the accompanying tables are indicated by the fos target to exemplify the useful anti-anaphylactic and anti-histamine acting properties of all the compounds of formula (I).

A. Materials and Methods.

a) Anti-anaphylactic and anti-histamine activity in vivo.

The anti-anaphylactic and anti-histamine effects of the compounds (I) and salts thereof have been studied in vivo in guinea pigs. Guinea pigs weighing between 400 and 500 g are made 30

DK 153477B

sensitive to ovalbumin by subplantar (s.p.) injection of 0/05 ml antiserum into the left hind paw. The animals are then sued and treated orally 24 hours after sensitization with saline (= control animals) or a specific dose of the compound during exploration.

The histamine injection (at a dose of 50 µg) is administered m.p. in the right hind paw 2 hours after oral pretreatment with the compound. The diameters of both hind legs are measured before the histamine injection is given and again 10 minutes thereafter. Animals are intravenously affected with 0.6 mg ovalbumin 30 minutes after histamine injection. All control animals develop typical primary anaphylactic shock symptoms (cough, difficulty breathing, convulsions), and 85% of these control animals die within 15 minutes of ovalbumin injection. Death protection is used as the criterion for possible drug effects, and the estimated ED the oral dose by which protection is observed in 50% of the guinea pigs is given in the tables below.

The median value of histamine-induced paw edema in 200 control animals 10 minutes after histamine injection is 15 units (1 unit = 0.1 mm); Reactions below 10 units occurring in less than 5% of control animals are defined as effective inhibition of histamine edema in the compound-treated animals, and the oral dose levels at which this effective inhibition is seen are also listed in the following tables.

b) Anti-histamine activity in vitro.

Guinea pig ileum strips are slurried in a 100 ml Tyrode bath at 37.5 ° C with a pre-introduced amount of 0.75 g and subjected to a gas of 95% C> 2 and 5% CC 2. The histamine-induced (0.5 mg / 1) spasms are chemically recorded with an isotonic lever which provides a 5-fold gain. The interaction between the compound to be tested (5 minutes incubation time) and the agonist is investigated, and the tables below provide the effective concentration (in mg / l) of the various compounds, thereby measuring a significant inhibition (50%) of the histamine-induced contraction.

31

DK 153477 B

As a result of the foregoing tests, the present compounds (I) and their pharmaceutically acceptable salts have usually been found to be active as anti-allergic agents in doses ranging from ca. 0.25 to approx. 20 mg / kg body weight by systemic administration to warm-blooded animals and humans.

In view of the useful antihistamine-acting and anti-anaphylactic activity of the compounds of the present invention, they may be formulated in various pharmaceutical forms for administration purposes. In preparing the present pharmaceutical compositions, an effective anti-histamine-acting or anti-anaphylactic amount of the particular compound in base or acid addition salt form is combined as the active ingredient in close admixture with a pharmaceutically acceptable carrier which may be in many different forms, depending of the formulation desired for administration.

These pharmaceutical compositions are desirable in unit dosage form which is preferably suitable for oral, rectal or parenteral injection. Eg. For example, in the preparation of the compositions in oral dosage form, any of the usual pharmaceutical media may be used, e.g. water, glycols, oils or alcohols in the case of oral liquid preparations such as suspensions, syrups, elixirs or solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders or disintegrants in the case of powders, pills, capsules and tablets. Because of the convenient administration of tablets and capsules, they constitute the most advantageous oral unit dosage form, thereby making it obvious that solid pharmaceutical carriers are 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 32

DK 153477 B

suspensions may also be prepared, whereby suitable liquid carriers, suspending agents or the like may be used. Acid addition salts of (I), because of their increased water solubility relative to the corresponding base form, are clearly more suitable in the preparation of aqueous compositions.

It is particularly advantageous to formulate the above-mentioned pharmaceutical compositions in unit dosage form for convenient administration and dosage uniformity. As used in the specification and claims herein, the term "unit dosage form" refers to physically separated units which are suitable as separate doses, each unit containing a predetermined amount of active ingredient which is intended to produce the desired therapeutic effect, together. with the necessary pharmaceutical carrier. Examples of such unit dosage forms are tablets (comprising slotted or coated tablets), capsules, pills, powder letters, cachets, injectable solutions or suspensions, teaspoons and tablespoons, and divided multiples thereof.

33 DK 153477 B

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The following examples are intended to illustrate the scope of the present invention. Unless otherwise stated, all parts therein are parts by weight.

Preparation of starting compounds

Example 1.

For a stirred and hot mixture of 54 parts of 1,3-dihydro-1- (phenylmethyl) -2H-benzimidazol-2-one, 47.25 parts of 1-bromo-3-chloropropari and 6 parts of Ν, Ν, Ν-triethylbenzene methanamine chloride 450 parts of sodium hydroxide solution are added dropwise 60% at 60 ° C. Upon completion, stirring is continued for 6 hours at 60 ° C. The reaction mixture is cooled and poured into water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane to give after drying 42 parts (58%) of 1- (3-chloropropyl) -1,3-dihydro-3- (phenylmethyl) -2H-benzimidazol-2-one.

Similarly, L-N 2 N- (CHO) -Cl 2/2 n was prepared

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L R H boiling point CH2 = C (CH3) 5-CH3 3 140 ° C at 0.015 mm. High pressure 5 'CH 2 = C (CH 3) 6-CH 3 3 140 ° C' r 0 ^ 02 mm. "" C6H5 5-.Cl 3 CH2 = C (CH3) H 4 CH2 = C (CH3) H 5 CH2 = C (CH3) H 6 43

Example 2.

DK 153477B

In accordance with the procedure of Example 1 and using an equivalent amount of a suitable 1H-benzimidazole as starting compound, a residue was obtained:

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Example 3

A mixture of 20 parts of 3 - [(2-amino-4-chlorophenyl) amino] -1-propanol, 50 parts of acetic acid and 150 parts of hydrochloric acid solution 4N is stirred and heated under reflux overnight. The reaction mixture is cooled and evaporated. The residue is dissolved in water and the solution is made alkaline with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane to give 6.5 parts (28%) of 5-chloro-2-methyl-1H-benzimidazole-1-propanol.

DK 153477B

44 Similarly, 5-chloro-2-ethyl-1H-benzimide-azole-1-propanol was prepared by reacting 3 - [(2-amino-4-chlorophenyl) amino] -1-propanol with propionic acid.

Example 4

To a stirred and heated reflux (water separator) mixture of 30 parts of 3 - [(2-amino-4-chlorophenyl) amino] -1-propanol and 0.1 part of 4-methylbenzenesulfonic acid in 405 parts of methylbenzene is added dropwise. solution of 34 parts cyclohexanecarboxaldehyde in 45 parts methylbenzene. Upon completion, stirring is continued for 1 hour at reflux temperature and under water separation. The methylbenzene is removed by evaporation in vacuo and the residue is triturated in 2,2'-oxy-bispropane. The product is filtered off and dried to give 16.5 parts (38%) of 5-chloro-2-cyclohexyl-1H-benzimidazole-1-propanol, mp 95 ° C.

Example 5

A mixture of 30 parts of 3 - [(2-amino-4-chlorophenyl) amino] -1-propanol, 44.8 parts of sodium α-hydroxybenzenesethanesulfonate and 120 parts of ethanol is stirred and heated under reflux for 30 minutes. The reaction mixture is evaporated and the residue is taken up in water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated to give 45 parts (100%) of 5-chloro-2- (phenylmethyl) -1H-benzimidazole-1-propanol as a residue.

Similarly, 6-chloro-2-cyclohexyl-1H-benzimidazole-1-propanol, m.p. 120.1 ° C, was prepared by reacting 3 - [(2-amino-5-chlorophenyl) amino] -1-propanol with sodium -A-hydroxycyklohexanmethansulfonat.

Example 6

To a stirred mixture of 93 parts of 3- (2-aminophenyl) amino-1-propanol, 45.5 parts of potassium hydroxide and 600 parts of ethanol 85% in water is added dropwise 60.8 parts of carbon disulfide. Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated and the residue is evaporated

DK 153477 B

taken in 1500 parts of water. The whole is filtered through "hyflo" and the filtrate is acidified with acetic acid. The oily product solidifies by scraping. It is filtered off, washed with water and dried to give 92 parts (78.9%) of 2-mercapto-1H-benzimidazole-1-propanol, mp 110 ° C.

A mixture of 20.8 parts of 2-mercapto-1H-benzimidazole-1-propanol, 15.62 parts of iodomethane and 120 parts of methanol is stirred overnight at room temperature. The reaction mixture is evaporated and the residue is dissolved in 500 parts of water. The solution is filtered through "hyflo" and the filtrate is made alkaline with solid potassium hydroxide. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated to give 19 parts (85.5%) of 2- (methylthio) -1H-benzimidazole-1-propanol as a residue.

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

Example 7

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 and 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 methylbenzene. The aqueous phase is separated and made alkaline with ammonium hydroxide. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated to give 50 parts of 1H-benzimidazole-1-butanol as an oily residue.

Example 8.

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46

To a stirred mixture of 5 parts of 4-chloro-1,3-dihydro-3- (3-hydroxypropyl) -2H-benzimidazol-2-one and 75 parts of trichloromethane is added dropwise 8 parts of sulfinyl chloride. Upon completion, stirring is continued for 3 hours at reflux temperature. The reaction mixture is cooled and evaporated. The residue is stirred in a small amount of 4-methyl-2-pentanone. The product is filtered off and dried to give 3/5 parts of 4-chloro-3- (3-chloropropyl) -1 / 3-dihydro-2H-benzimidazol-2-one.

Similarly, the following 1- (chloroalkyl) -1H-benzimidazoles were prepared: é- (CH2) n-Cl 7 'V 6 Μ n R 1 -C1 base

ø 3 5-C1 In HCl 211; 7 ° C

C6H5 ~ CH2 3H base 112 ° C

41

DK 153477 B

M n R1 melting point

<6> 3 6-Cl HCl 227/5 ° C

C2H5 2 H base H 4 H base -

Example 9

A mixture of 113.2 parts of 1,2,4-trichloro-5-nitrobenzene, 75 parts of 3-amino-1-propanol, 0.2 parts of potassium iodide and 200 parts of butanol is stirred and heated under reflux overnight. The butanol is removed by evaporation in vacuo and water is added to the residue. The product is extracted with 4-methyl-2-pentanone. The extract is washed a few times with water, dried, filtered and evaporated. The oily residue is purified by column chromatography through silica gel using a mixture of trichloromethane and 5% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of 2,21-oxybispropane and 2-propanol to give 31.7 parts of 3 - [(4,5-dichloro-2-nitrophenyl) amino] -1-propanol, m.p. 97 ° C .

Similarly: 3- I [2-nitro-4- (trifluoromethyl) phenyl] amino] -1-propanol, and 2- I [2-nitro-4- (trifluoromethyl) phenyl] amino] ethanol, m.p. 9 ° C.

Example 10.

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

DK 153477B

48 sulfinyl chloride (exothermic reaction: temperature rises to 45 ° C). Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated to give 43 parts (100%) of N- (3-chloropropyl) -2-nitrobenzenamine as a residue.

Similarly: N- (3-chloropropyl) -2-nitro-4-trifluoromethyl) benzenamine was prepared as a residue, 4,5-dichloro-N- (3-chloropropyl) -2-nitrobenzenamine, m.p. 78 ° C, and N- (2-chloroethyl) -2-nitro-4- (trifluoromethyl) benzene amine. Example 11.

A mixture of 21.5 parts of N- (3-chloropropyl) -2-nitrobenzenamine, 22.68 parts of 1- (diphenylmethyl) -piperazine, 20 parts of N, N-diethylethanamine and 180 parts of Ν, Ν-dimethylacetamide is stirred and heated in 6 hours at 100 ° C. The reaction mixture is evaporated and the residue is taken up in water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanol, ethanol and 2,2'-oxybispropane. The product is filtered off and dried to give 15.5 parts (36.9%) of 4- (diphenylmethyl) -N- (2-nitrophenyl) -1-piperazine propanamine hydrochloride, mp 228 ° C.

Similarly, N- (4,5-dichloro-2-nitrophenyl) -4- (diphenylmethyl) -1-piperazine propanamine was prepared as a residue, 4- (diphenylmethyl) -N- [2-nitro-4- (trifluoromethyl) -phenyl] -1-piperazine propanamine, m.p. 113.7 ° C, and 4- (diphenylmethyl) -N- [2-nitro-4- (trifluoromethyl) phenyl] -1-piperazinethanamine, mp 152.1 ° C.

Example 12.

A mixture of 15 parts of 4- (diphenylmethyl) -N- (2-nitrophenyl) - 49)

DK 153477 B

1-piperazinepropanamine / hydrochloric! in 160 parts of methanol is 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 at "hyflo" and the filtrate is evaporated. The solid residue is crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product is filtered off and dried to give 12 parts (78.9%) of N- (2-aminophenyl) -4- (diphenylmethyl) -1-piperazine propanamine, hydrochloride, mp 223.1 ° C.

Similarly, 4,5-dichloro-N 2 - [3- (4- (diphenylmethyl) -1-piperazinyl] propyl] -1,2-benzenediamine was prepared as an oily residue N diphenyl) -1-piperazinyl] propyl] -4- (trifluoromethyl-1,2-benzenediamine, and N- [2- [4- (diphenylmethyl) -1-piperazinyl] ethyl] -4- (trifluoromethyl) - 1,2-Benzenediamine as an oily residue.

Example 13

A mixture of 60.5 parts of 1- (3-chloropropyl) -1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazol-2-one, 31.68 parts of 1- (phenylmethyl) piperazine, 21.2 parts sodium carbonate, 0.1 parts potassium iodide and 400 parts 4-methyl-2-pentanone are stirred and heated at reflux for 20 hours under water separation. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated to give 70 parts (100%) of 1,3-dihydro-1- (1-methylethenyl) -3- [3- [4- (phenylmethyl) -1-piperazinyl] propyl] -2H benzimidazol-2-one as a residue.

Similarly, 1,3-dihydro-1- [2- (4- (phenylmethyl) -1-piperazinyl] ethyl] -2H-benzimidazol-2-one, m.p. 136.5 ° C was prepared.

Example 14.

To a stirred solution of 70 parts of 1,3-dihydro-1- (1-methyl-ethenyl) -3- [3- [4- (phenylmethyl) -1-piperazinyl] -propyl] -2H-

DK 153477 B

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

Example 15

A mixture of 63 parts of 1,3-dihydro-1- [3- [4- (phenylmethyl) -1-piperazinyl] propyl] -2H-benzimidazol-2-one in 400 parts of methanol is hydrogenated at 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 at "hyflo" and the filtrate is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2-propanol. The product is filtered off and dried to give 29.5 parts (63%) of 1,3-dihydro-1- [3- (1-piperazinyl) propyl] -2H-benzimidazol-2-one, mp 157.5 ° C.

Similarly prepared: 1,3-dihydro-1- [2- (1-piperazinyl) ethyl] -2H-benzimidazol-2-one, m.p. 122.6 ° C.

Example 16.

To a stirred mixture of 20 parts of aluminum chloride and 100 parts of fluorobenzene is added dropwise 20.5 parts of 2,4-dichlorobenzoyl chloride. Upon completion, the mixture is heated to reflux and stirred at reflux temperature for 5 minutes. The reaction mixture is poured onto crushed ice and the product is extracted with 1,1'-oxybisethane. The extract is dried and evaporated to give 30 parts (2,4-dichlorophenyl) (4-fluorophenyl) methanone as an oily residue.

Similarly, (4-fluorophenyl) (4-pyridinyl) methanone, m.p. 85.5 ° C was prepared.

51

DK 153477 B

Example 17

To a stirred and refluxed mixture of 23.4 parts (4-chlorophenyl) (2-fluorophenyl) methanone in 280 parts of 2-propanol is added portionwise. 3.7 parts sodium borohydride. Upon completion, stirring is continued for 2 hours at reflux temperature (- 80 ° C). The reaction mixture is cooled and cleaved by the addition of water. The 2-propanol is evaporated and the residue product is extracted with trichloromethane. The extract is dried, filtered and evaporated to give 23.6 parts of 4-chloro-α- (2-fluorophenyl) benzene methanol as a residue.

Similarly, 2,4-dichloro-α- (4-fluorophenyl) benzene methanol was prepared as a residue, <x- (4-fluorophenyl) -4-pyridinemethanol, mp 138.2 ° C, α- (4-fluorophenyl) -3-pyridine methanol, hydrochloride, mp 158.3 ° C, and 4-methoxy-α- [3- (trifluoromethyl) phenyl] benzene methanol as a residue.

Example 18.

A mixture of 22 parts of 2,4-dichloro-α- (4-fluorophenyl) benzene methanol and 240 parts of hydrochloric acid solution 12N is stirred for 40 hours at room temperature. The reaction mixture is poured into ice water and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is distilled to give 13.2 parts of 2,4-dichloro-1- [chloro- (4-fluorophenyl) methyl] benzene, boiling point 146 ° C at 0.15 mm Hg pressure.

Similarly, 1- [α-chloro-α- (4-methoxyphenyl) methyl] -3- (trifluoromethyl) benzene was prepared as a residue, and 1- [chloro- (4-methylphenyl) methyl] -4-fluorobenzene as a remnant.

Example 19.

DK 153477 B

5.2

To a stirred mixture of 23.6 parts of 4-chloro-α- (2-fluoro-phenyl) benzene methanol in 108 parts of benzene is added dropwise 24 parts of sulfinyl chloride. Upon completion, the whole is heated to reflux and stirring is continued for 5 hours only at reflux temperature and further overnight at room temperature. The benzene is evaporated and the residue distilled off to give 16.5 parts of 1-chloro-4- [α-chloro-ct- (2-fluorophenyl) methyl] benzene, bp 122-125 ° C at 0.1 mm Hg pressure.

Similarly: 3- [α-chloro-α- (4-fluorophenyl) methyl] pyridine, hydrochloride as an oily residue, 3- [α-chloro-α- (4-chlorophenyl) methyl] pyridine, hydrochloride as a residue, 4- [α-chloro-α- (4-fluorophenyl) methyl] pyridine, hydrochloride, m.p. 198-200 ° C, 1- (chlorophenylmethyl) -2,3-dimethylbenzene, boiling point 137 ° C at 0.7 mm Hg pressure, 1- (chlorophenylmethyl) -2,4-dimethylbenzene, boiling point 137 ° C at 0, 7 mm Hg pressure 2- (chlorophenylmethyl) -1,4-dimethylbenzene, boiling point 136 ° C at 0.7 mm Hg pressure, 1- (chlorophenylmethyl) -2-fluorobenzene, bp 108-109 ° C at 0.4 mm Hg pressure.

Example 20

A mixture of 121 parts of piperazine, 54 parts of 3- [α-chloro-α- (4-chlorophenyl) methyl] pyridine, hydrochloride and 315 parts of N, N-dimethylformamide is stirred for 20 hours at room temperature. The reaction mixture is evaporated and 250 parts of water is added to the residue. The product is extracted with methylbenzene. The organic phase is washed with water and extracted with 10% acetic acid solution. The acidic aqueous phase is made alkaline with a sodium 53,

DK 153477 B

hydroxide solution 60% and the product is extracted again with methylbenzene. The extract is dried, filtered and evaporated. The oily residue is converted to the nitrate salt in ethanol. The salt is filtered off, washed with ethanol and with 2,2'-oxybis-propane and crystallized from ethanol to give 48 parts of 1- [α- (4-chlorophenyl) -a- (3-pyridinyl) methyl] piperazine, trinitrate, m.p. 132.9 ° C.

Similarly: 1- [α- (4-chlorophenyl) -α- (2-fluorophenyl) methyl] piperazine, 1- [α- (4-fluorophenyl) -α- (4-pyridinyl) methyl] piperazine, m.p. 108.4 ° C, 1 - [(2-chlorophenyl) (3-chlorophenyl) methyl] piperazine, 1 - [(2-fluorophenyl) phenylmethyl] piperazine, oxalate (1: 1), m.p. 195.5 ° C, 1 - [(4-fluorophenyl) (4-methoxyphenyl) methyl] piperazine, oxalate (1: 2), mp 280.1 ° C and 1 - [(4-nitrophenyl) phenylmethyl] piperazine, dihydrochloride. Example 21.

A mixture of 21.5 parts of ethyl 4-hydroxy-1-piperidine carboxylate, 35.2 parts of bis (4-fluorophenyl) broramethane and 8.6 parts of potassium carbonate is stirred and heated in an oil bath at 140 ° C for 3 hours. The reaction mixture is allowed to cool to room temperature and water is added. The product is extracted with methylbenzene. The extract is washed successively with water, a dilute hydrochloric acid solution and a sodium hydrogen carbonate solution, dried, filtered and evaporated. The process is equilibrated (boiling point to 143 ° C at 0.5-1 mm Hg pressure) to give 29 parts of ethyl 1- [bis (4-fluorophenyl) methoxy] -1-piperidinecarboxylate as an oily residue.

Similarly: ethyl 4- (diphenylmethoxy) -1-piperidinecarboxylate, boiling point 150 ° C at 0.4 mm Hg pressure was prepared.

Example 22.

DK 153477 B

54

A mixture of 29 parts of ethyl 4- [bis (4-fluorophenyl) methoxy] -1-piperidinecarboxylate, 25 parts of potassium hydroxide, 1 part of water and 160 parts of 2-propanol is stirred and heated under reflux for 4 hours. The solvent is evaporated and water is added to the residue. The product is extracted with methylbenzene. The extract is washed a few times with water, dried, filtered and evaporated. The oily residue is converted to the hydrochloride salt in 4-methyl-2-pentanone and 2-propanol at room temperature. The salt is filtered off and dried to give 20.5 parts (78%) of 4- [bis (4-fluorophenyl) methoxy] piperidine, hydrochloride, mp 161.8 ° C.

Similarly: 4- (diphenylmethoxy) piperidine, hydrochloride, m.p. 209.8 ° C was prepared.

Manufacture of end products

Example 23

A mixture of 5.3 parts of 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one, 5 parts of 1- (diphenylmethyl) piperazine, 6.4 parts of sodium carbonate and 200 parts of 4-methyl 2-pentanone is stirred and heated under reflux overnight under water separation. After cooling, water is added and the layers are separated. The 4-methyl-2-pentanone phase is dried, filtered and evaporated. The residue is purified by column chromatography through silica gel using a mixture of trichloromethane and 5% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from a mixture of 2,21-oxybispropane and a small amount of 2-propanol. The product is filtered off and dried to give 2 parts (23%) of 1- [3- (4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-1

'o J

2H-benzimidazol-2-one, mp 153.6 ° C

Similarly, the following compounds were prepared in free base form or in the form of an acid addition salt after treatment of the free base with a suitable acid:

DK 153477B

-P I

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DK 153477B

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DK 153477 B

57 +) Λί

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Example 24.

DK 153477B

In a manner analogous to that described in Example 23, 1-13- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] -propyl] -1,3-dihydro-2H-benzimidazole 2-one, mp 197.3 ° C by reacting 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one, methanesulfonate with 1- [bis (4-fluorophenyl) methyl] piperazine, 1-I 3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-3-methyl-2H-benzimidazol-2-one, dihydrochloride, hydrate, m.p. 201.8 ° C by reaction of 1 , 3-dihydro-1- (3-iodopropyl) -3-methyl-2H-benzimidazol-2-one with 1- (diphenylmethyl) piperazine, 3- ^ 3- [4- (diphenylmethyl) -1-piperazinyl] propyl | -2 (3H) -benzothiazolone, dihydrochloride, hemihydrate, mp 186.1 ° C by reaction of 3- (3-bromopropyl) -2 (3H) -benzothiazolone with 1- (diphenylmethyl) -piperazine, and 3- £ 3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -2 (3H) -benzoxazolone, dihydrochloride, m.p. 212.4 ° C by reacting 3- (3-chloropropyl) -2 (3H) -benzoxazolone with 1- ( diphenylmethyl) piperazine.

Example 25

A mixture of 6.95 parts of 1- (5-chloropentyl) -1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazol-2-one, 5.15 parts of 1- (diphenylmethyl) piperazine, 5, 30 parts of sodium carbonate, 0.1 parts of potassium iodide and 160 parts of 4-methyl-2-pentanone are stirred and heated under reflux overnight under water separation. The reaction 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 for 30 minutes with 12 parts of a hydrochloric acid solution in 40 parts of ethanol. The whole is evaporated and the residue is crystallized from ethanol to give 5 parts (46%) of 1- [5- (4- (diphenylmethyl) -1-piperazinyl] pentyl] -1,3-dihydro-2H-benzimidazol-2-one , dihydrochloride, hydrate, m.p. 215.3 ° C.

DK 153477 B

59 Similarly prepared: / - \

HN N- (CH 2) -N tt-CH

^ 2nwx-2 ή Ar1 Ar2 Base ”or Melting

r salt form · point in ° C

5 4_f-C6H4 4-P ~ C6H4 2HC1.H2O 203.7.

4 C6H5 4-F-C6H4 base 172.3 '3' C6H5 2-C1-C6H4 base 149 3 3-C1-C6H4 2-C1-C6K4 base.H20 139.1 3 C6H5 2,4-Cl2 base 160, 1 C6H3 6 C6H5 C6H5 base 189.7 6 4-F-CgH4 4-F-C6H4 2HC1 204.5

Example 26

To a stirred solution of 76 parts of 1- [3- (4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazol-2-one in 280 parts ethanol is added 120 parts hydrochloric acid solution and 250 parts water. It is all stirred for 30 minutes at room temperature. After cooling in an ice bath, the product precipitates.

It is filtered off, washed with 2-propanone and with 2,2'-oxybis-propane and dried to give 43 parts (55%) of 1- [3- (4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3 -dihydro-2H-benz-imidazol-2-one, dihydrochloride, hydrate, mp 237.5 ° C.

Similarly prepared: 60

DK 153477B

O 1 X / - \ / Ar1 HN N-C H „-N N-CH 0 4 ^ S7 w ^ Ar • R1 RV CnH2n __ ^ Γ%.

H (CH2) 3-pyridinyl 4-C1-CgH2 160.2 H (ch2) 3 4-pyridinyl 4-F-CgH4 183.2 H (ch2) 3 4-Cl-cgH4 4-OCH3-C6H4199.3 H (CH2) 3 C6H_2-F-C6H4 157.7 5- CH3 (CH2) 3 C6H5 C6H5 178.3 6- CH3 (CH2) 3 C6H5 C6H5 195.7 H CH3-CH (CH3) -4-F C6H4 4-F-C6H4 176 ch2

Example 27

A mixture of 3.6 parts of N 2 - [2- [4- (diphenylmethyl) -1-piperazinyl] ethyl] -4- (trifluoromethyl) -1,2-benzenediamine and 1.8 parts of urea is stirred for 3 hours in an oil bath at 190 ° C. The reaction mixture is cooled, water and trichloromethane are added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography through silica gel using a mixture of trichloromethane and methanol (95: 5) as eluent. The pure fractions are collected, the eluent is evaporated to give 1.5 parts (41.5%) of 1- [2- [4-diphenylmethyl) -1-piperazinyl] ethyl] -1,3-dihydro-5- (trifluoromethyl) ) -2H-benzimidazol-2-one, mp 163.7 ° C.

Similarly prepared: 1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-5- (trifluoromethyl) -2H-benzimidazol-2-one, mp 152.7 ° C, 61

DK 153477 B

and

5,6-Dichloro-1- [3- [4- (diphenylmethyl) -1-piperazinyl] -) L

propyl -1,3-dihydro-2H-benzimidazol-2-one, mp 214.7 ° C.

Example 28.

A mixture of 2.3 parts of 1- in 3- [4- (diphenylmethyl) -1-) piperazinyl] propyl] -1,3-dihydro-2H-benzimidazol-2-one, 4.5 parts of formaldehyde solution 40% and 45 parts Ν, Ν-Dimethylformamide is stirred and heated for 2 hours at 100 ° C. The reaction mixture is cooled and diluted with water. The precipitated product is filtered off and crystallized from methylbenzene to give 1.5 parts (66%) of 1- [3- (4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-3- ( hydroxymethyl) -2H-benzimidazol-2-one, mp 102.5 ° C.

Example 29.

A mixture of 1.55 parts acetic anhydride, 3 parts 1- [3- (4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-2H-benzimidazol-2-one and 22.5 parts methylbenzene is stirred. and heated at reflux overnight. Water is added to the reaction mixture and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography through silica gel using a mixture of trichloromethane and methanol (95: 5) as eluent. The pure fractions are collected and the eluent is evaporated to give 1.1 parts (33.5%) of 1-acetyl-3- [3- (4- (diphenylmethyl) -1-piperazin-yl] propyl] -1,3-dihydro -2H-benzimidazol-2-one, mp 124.4 ° C.

Example 30.

A mixture of 1.1 parts of ethyl 2-propenoate, 3 parts of 1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-2H-benzimidazol-2-one, a few drops Ν, Ν, Ν-trimethylbenzene-methanaminium hydroxide solution 40% in methanol and 25 parts of 1,4-dioxane are stirred and heated under reflux for 24 hours.

62

DK 153477B

The reaction mixture is evaporated. The residue is purified by column chromatography through silica gel using a mixture of trichloromethane and methanol (95: 5) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to the hydrochloride salt in 2-propanol and ethanol. The salt is filtered off and dried to give 1.4 parts (32.5%) of ethyl 3- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -2,3-dihydro-2-oxo-1H-benzimidazole -1-propanoate, dihydrochloride, dihydrate, mp 204 ° C.

Example 31.

A mixture of 3 parts of 1- [3- (4- (diphenylmethyl) -1-piperazin-yl] propyl] -1,3-dihydro-2H-benzimidazol-2-one, 1 part of isocyanato-methane and 25 parts of 1.4 -dioxane is stirred and heated under reflux overnight. The reaction mixture is evaporated and the residue is purified by column chromatography through silica gel using a mixture of trichloromethane and methanol (95: 5) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of methylbenzene and 2,2T-oxybispropane to give 0.8 parts (23.5%) of 3- [3- (4- (diphenylmethyl) -1-piperazinyl] propyl] -2,3-dihydro-2 N-methyl-2-oxo-1H-benzimidazole-1-carboxamide, mp 153.1 ° C.

Example 32.

To a stirred mixture of 9.4 parts of 1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-2H-benzimidazol-2-one and 180 parts of methylbenzene is added 0.8 parts of sodium hydride dispersion 75% and the whole is stirred and heated for 60 minutes at 90 ° C. After cooling to 30 ° C, 0.2 parts of 2.3, 11, 12-dibenzoe-1, 4,7, 10,13,16-hexacyclooctadeca-2, 11-diene are added and stirring is continued for 10 minutes. Then 4.2 parts of ethyl 2-bromoacetate are added and the mixture is stirred and heated under reflux overnight. The reaction mixture is cooled to 90 ° C, 50 parts water is added and the layers are separated while warm. The organic phase is evaporated to give 10 parts of ethyl 3- [3- (4- (diphenyl

DK 153477 B

methyl) -1-piperazinyl] propyl | -2,3-dihydro-2-oxo-1H-benz-imidazole-1-acetate as a residue.

A mixture of 9.8 parts of ethyl 3- [3- (4- (diphenylmethyl) -1-piperazinyl] propyl] -2,3-dihydro-2-oxo-1H-benzimidazole-1-acetate, 1.2 parts of sodium hydroxide and 150 parts of water are stirred and heated under reflux for 5 minutes (+ 8 ° C). The reaction mixture is filtered and the filtrate is acidified with acetic acid to pH 5.8-6; a sticky precipitate forms. It is separated and crystallized from ethanol and water. The product is filtered off and dried in vacuo at 100 ° C for 3 hours to give 3- [3- (4- (diphenylmethyl) -1-piperazinyl] propyl] -2,3-dihydro-2-oxo-1H-benzimidazole-1- acetic acid, hemihydrate, mp 138.7 ° C.

Example 33

A mixture of 5.2 parts of 1,3-dihydro-1- [3- (1-piperazinyl) propyl] -2H-benzimidazol-2-one, 5.28 parts of 2- (chlorophenylmethyl) pyridine, hydrochloride, 5 , 3 parts sodium carbonate and 90 parts N, N-dimethylformamide are stirred and heated overnight at 50 ° C. The reaction mixture is cooled and poured into ice water. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried to give 2 parts (23.4%) of 1,3-dihydro-1- [3- [4- [phenyl (2-pyridinyl) methyl] -1-piperazinyl] propyl] -2H-benzamide imidazol-2-one, mp 141.7 ° C.

Similarly prepared: X r- \ s · **

Hitrite (CEL) o-N N-C H

8 64

DK 153477B

1 P Λ

Ar Ar snip, in ° c.

154.1 3- Pyridinyl 162.6 4- F-C6H4 4-CH3-C6H4 147.8 4-C1-C6H4 4-C1-C6H4 209.5 4-F-C6H4 2 , 4-Cl2-C6H3 160.1

CgH2 2,3- (CH3) 2- 169.8 C6H3 3-cf3-c6h4 4-OCH3-CsH4 153.4 C6H5 4-CH3-C6H4 178.3

CgH2 2.4- (CH3) 2- 115.8 C6H3 C6h5 2.5- (CH3) 2- 156.3 C6H3

Example 34

Using appropriate starting materials and in the manner described under process variant (a), were prepared: H Ar1 5 Τ '6

6s DK 153477 B

-P

M

fi in cn co co cm cm κ p> O co co f- Ch co a) co ^ (j \ cm crv • P · <r- v- r- r- T- r-.-4 O 0) 0 ε CQ · Η ® ° cm 0α] Ο d ^ <u <ϋ κ <y æ cm OM 2 2 2 «ο κ ω 5 (0« 5 · * ΰ · ·, ιΗ, Q, Q Η / 3 Η Η Λ , Tj Ο Ο Ο νϋ Ή ►τ «» -tc> -r <mr — 1 »-µ tX. I-Lh“ o CO co 00 ffl 0) <M m in m in in a ra aaaaa

«Ρ VO VO CO VO VO MO

^ '0 0 0.0 0 0. ^ in in in in in in 5 K a a X K fi

VO VD VD VO VO CD

O O O O O O

CO CO CM CO CO CO

CM '~ Ci ^ CM ^ * CM CM CM CM

a and w κ a a a

β ο ο ο ο o

Q V 'V.—'> / V / '- ^ v— ^

Η Η H

r- 0 0.0 «I 11 a in a m a in • cm CM« ffi O O I 1 in in m in in s a a w «w w

VO VO VO VD ΛΟ VO

o o o o o o

66 DK 153477 B

JJ

£ in σ \ ιο

ft VO CO

$ Ο Γ- t>

i-l u (UO

e cn ή u Q) h g ai Q) ω <u Π to to o «5 id id I tw rQ, Q £) 0) -P to H (d td m to in in cm a a a

in VO VO VO

<3000 in in a r- a a a

VO VO VD

cuoo co co co

CM CM CM CM

a a a a a s o o o O v- 'w w

H iH

Island Island

r ~ I I

a a m vo s 10.0 0.

67

DK 153477B

Example 35.

In accordance with the procedure of Example 34, 1- [3- (4- (diphenylmethyl) -1-piperazinyl] propyl} -2- (methylthio) -1H-benzimidazole, trihydrochloride, hydrate, m.p. 203.4 ° C 3- [2- (methylthio) -1H-benzimidazol-1-yl] propylmethanesulfonate with 1- (diphenylmethyl) -piperazine.

Example 36.

A mixture of 4.37 parts of N- (2-aminophenyl) -4- (diphenylmethyl) -1-piperazine propanamine, hydrochloride, 38 parts of carbon disulfide, 2 parts of sodium carbonate and 40 parts of ethanol is stirred and heated under reflux for 20 hours. The reaction mixture is evaporated and water is added to the residue. The precipitated product is filtered off, washed with water and dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone to give 2 parts (45.5%) of 1- [3- (4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-2H-benzimidazole-2 -thione, mp 181.8 ° C.

Example 37.

A mixture of 60 parts of N- (2-aminophenyl) -4- (diphenylmethyl) -1-piperazine propanamine, 20 parts of methyl (iminomethoxymethyl) carbamate, 42 parts of acetic acid and 450 parts of trichloromethane is stirred and heated under reflux overnight. The reaction mixture is evaporated and the residue is stirred in water. The latter is decanted off and the residue is taken up again in water. The whole is made alkaline with a dilute ammonium hydroxide solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography through silica gel using a mixture of trichloromethane and methanol (95: 5) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane to give 13.5 parts of methyl- [1- [3- (4- (diphenylmethyl) -1-piperazinyl] propyl] -1H- benzimidazol-2-yl] carbamate, mp 137.8 ° C.

DK 153477 B

68

A mixture of 12 parts of methyl [1- [3- (4- (diphenylmethyl) -) c1-piperazinyl] propyl] -1H-benzimidazol-2-yl] carbamate, 60 parts of a concentrated hydrochloric acid solution and 80 parts of ethanol is stirred. heated at reflux overnight. The reaction mixture is evaporated and water is added to the residue. The free base is conventionally released with ammonium hydroxide and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from ethanol. The product is filtered off and dried to give 4.3 parts (40%) of 1- [3- (4- (diphenylmethyl) -1-piperazinyl] propyl] -1H-benzimidazol-2-amine, mp 228.7 ° C.

A mixture of 10.7 parts of 1- (3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -1H-benzimidazole-2-amine, 5.1 parts of acetic anhydride and 90 parts of methylbenzene is stirred and heated under reflux. The reaction mixture is evaporated and the residue is stirred in water. The whole is made alkaline with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from ethanol. 56.5%) N- [1- [3- (4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-2H-benzimidazol-2-ylideneacetamide, m.p. 143.3 ° C.

Example 38

A mixture of 13 parts of 1,3-dihydro-1- [3- (1-piperazinyl) propyl] -2H-benzimidazol-2-one, 12.4 parts of 1,1 - (bramethylene) bis [benzene] , 6.6 parts sodium carbonate and 200 parts 4-methyl-2-pentanone are stirred and heated at reflux overnight under water separation. After cooling to room temperature, water is added and the layers are separated. The organic layer is dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol to give 1- [3- [4- (diphenylmethyl) -1-piperazinyl] -propyl] -1,3-dihydro-2H-benzimidazole -2-one, mp 153 ° C.

Example 39

In accordance with the procedure of Example 38 and below

DK 153477 B

69 using equivalent amounts of the appropriate starting materials, the following compounds are prepared: 1- [2- [4- (bis (4-fluorophenyl) methyl] -1-piperazinyl] -ethyl] -1,3-dihydro-2H-benzimidazole 2-one, hemihydrate, mp 131.5 ° C, 1- [2- [4- (diphenylmethyl) -1-piperazinyl] ethyl] -1,3-

/ Q

dihydro-2H-benzimidazol-2-one, m.p. 218 ° C, and 1- [3- [4- [bis- (4-fluorophenyl) methyl] -1-piperazinyl} propyl] -1,3-dihydro-2H benzimidazol-2-one, m.p. 198 ° C.

Example 40 ♦

A mixture of 4.8 parts of 1- (3-chlorophenyl) -1,3-dihydro-2H-benzimidazol-2-one, 6.1 parts of 4- (diphenylmethoxy) piperidine, hydrochloride, 7.5 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone are stirred and heated under reflux overnight under water separation. The reaction mixture is cooled and water is added. The layers are separated and the 4-methyl-2-pentanone phase is dried, filtered and evaporated. The oily residue is purified by column chromatography through silica gel using a mixture of trichloromethane and 5% methanol as eluent.

The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone to give 4.2 parts (48%) of 1- [3- (4- (diphenylmethoxy) -1-piperidinyl] propyl} -1,3-dihydro-2H-benzimidazole -2-one, m.p. 149.2 ° C.

Similarly,: / Ar1 B- (CH2) n-Q-O-® ^ 2 was prepared

DK 153477 B

70 B n Ar "5 Ar2 '3ase ~ or smg.

salt form 'in DC

—— 2 C6H5 C6H5 HC1 253/1 "3 4-F-C6H4 4-F-C6H4 HC1 1/2 167.2 H20" 2 4-F-C6H4 4-F ~ C6H4 HC1 1/2 251.4 H2O 4 C6H5 C6H5 base 152 N ^ N- 3 CgH5 C6H5 base 110.2 o ___J_J_I -

Claims (8)

An analogous process for the preparation of 1-substituted 4- (diarylmethyl) piperazine or 1-substituted 4- (diarylmethoxy) piperidine derivatives having the general formula: - / - Ar1, (I) acceptable acid addition salts thereof, wherein: 1 2 Ar and Ar are each a group in the form of phenyl, substituted phenyl or pyridinyl, wherein the substituted phenyl is phenyl with from 1 to 2 substituents each in the form of halogen, C 1-6 alkyl, C 1-6 alkyloxy, tr if luorme thyl or nitro, m "is the integer 0 or 1, A is a group in the form of or -, provided that m is 0 when A is and m is 1 when A is ^ CH -, n is an integer of 2 to 6 inclusive, provided that at least 2 carbon atoms are present in the linear portion of the chain connecting B to piperidine or the piperazine nitrogen atom when CnH2n represents a branched alkylene chain and B is a group in the form of: a) a group of the general formula: A. R1 R2 Wherein R and R are each an atom or group in the form of hydrogen, halogen, C 1-6 alkyl or trifluoromethyl, and Y is an atom or group in the form of oxygen, sulfur or substituted nitrogen wherein: L is an atom or group in the form of hydrogen, C 1-4 alkyl, C 1-4 alkylcarbonyl, g alkyloxycarbonylalkyl, carboxy-C 1-6 alkyl, phenyl, phenylmethyl, C 1-6 alkylaminocarbonyl, hydroxymethyl or C when Y is oxygen or sulfur, R 1 and R 2 are both hydrogen, Ar and Ar 2 are both phenyl, A is N and N is 3, or b) a group of the general formula: R and R are each an atom or group in the form of hydrogen, halogen, C1-6 alkyl, or trifluoromethyl, and M is an atom or group in the form of hydrogen, C1-6 alkyl, phenyl, phenylmethyl , mercapto, C 1-6 alkylthio, amino, C 1-6 alkylcarbonylamino, C 1-6 alkyloxycarbonylamino or cycloalkyl having from 3-6 carbon atoms, provided that M is other than hydrogen or C -g-alkyl, when ^ A-is ^ N- characterized by: a) reacting an appropriate reactive ester having the general formula: B'-CnH2n-W (II '> wherein n is as previously defined; and B 'is the same as B above except a 2-amino-1H-benzimidazol-1-yl group, such as R and R have the meanings set forth above and W is an appropriate reactive ester function derived from the corresponding alcohol, with a compound having the general formula: - - - / Ap1 HN A- (O) -CH (III) m \ Δ 2 Ar 1 2 wherein A, m, Ar and Ar have the meanings previously stated, preferably in the presence of a reaction inert organic solvent and a suitable base, and at elevated temperatures to produce a compound having the general formula: Ar 2 B '- CnH 2 n (0) m- ™ d'1 W ^ Ar2 1 2 wherein B ', η, A, m, Ar and Ar have the meanings previously stated and, if desired, decarboxylate a compound thus prepared having the general formula DK 153477 B ^ H COO C 6) alkyl N ^ N-CH-V V (o) --CH * y / 112,1 \ _y m ^ 4,2 Q R1 R2 12 12 wherein R, R, n, A, m, Ar and Ar has the meanings previously stated under hydrolytic conditions to produce a compound having the general formula: NH "AT1 I2 / -V s * · fC> -Cn! I2n-liwA- (O)" 'C® 2 da) H Y- \ 2 R1 R ^ 12 12 wherein R, R, η, A, m, Ar and Ar have the meanings previously stated, or b) ring terminates a compound having the general formula Ar1 · h2N NH- CnH2n-tQA- (0) m-CH Q R2 12 12 wherein R, R, η, A, m, Ar and Ar have the previously stated meanings, with a suitable ring closure means well known in the art by well known methodology for preparing a compound, which has the general formula DK 153477 B (L / - \ / Αρ1 -1 / A- (0) -CH, T, \ _ / n 2n \ _ / m \ 2 '(Ι-c) Ar' r1 r2 io 12 wherein R, R, η, A, m, Ar and Ar have the previously mentioned meanings, or for the preparation of a compound having the general formula. f ^ H W XAr2 (M) R1 R2; lo 12 wherein R, R 1, η, A, m, Ar and Ar have the previously mentioned terms and are: an atom or group in the form of hydrogen, C 1 -C 8 alkyl, phenyl, phenylmethyl 1, mercapto, or c) removes one protecting group P, depending on its type, with acidic or alkaline hydrolysis from a compound having the general formula JL r- Arl P-0-CAa-0 '(0)' '\ 2 (V) <r \ Ar R1 R2 DK 153477 B 12 12 wherein R, R, η, A, m, Ar and Ar have the meanings previously stated for Preparation of a Compound Having the General Formula? \ - ^ ^1 HN ^ CxN-C H_ -N A- (O) -CH w »W - XAr2 12 12 wherein R, R, η, A, m, Ar and Ar has the meanings previously stated, or d) acylates a suitable compound having the general formula (Ia) above by standard N-acylation processes to prepare a compound having the general formula NH-CO- (lower alkyl) If--CnH₂n-I (3'i0) '' C ^ \ Ar2 (ie) R1 R2 12 12 wherein R, R, η, A, m, Ar and Ar have the meanings previously set forth, or e) introduce a group by well known methods into a compound having the general formula (Ic) above to prepare a compound having the general formula In which R, R, η, A, m, Ar and Ar have the meanings previously stated, and are a group in the form of. C 1-6 alkyl, C 1-6 alkylcarbonyl ,. C1-6 alkyloxycarbonyl- C1-6 alkyl, carboxy-C1-6 alkyl, phenylmethyl, C1-6 alkylaminocarbonyl, hydroxymethyl or C2-6 alkenyl, provided that this C2-6 alkenyl is unsaturated at a position different from a- or (f) condenses a compound having the general formula / BH-N NH n 2n \ _ / (XVI) wherein B and n have the previously stated meanings with a suitable reactive ester having the wherein W, Ar and Ar have the meanings previously set forth, preferably in the presence of a reaction inert organic solvent and a suitable base, and at elevated temperatures to prepare a compound having general formula DK 153477 B AT1 'B-CnH2n-NO2 € 2 dg) AT1 2 wherein B, n. Ar and Ar have the previously stated meanings and, if desired, produce pharmaceutically acceptable acid addition salts of the products of step a) - f). A process according to claim 1 for the preparation of 1- [3- (4-diphenylmethyl) -1-piperazinylpropyl] -1,3-dihydro-3 H -benzimidazol-2-one or the pharmaceutically acceptable acid addition salts thereof, characterized in reacting 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one with 1- (diphenylmethyl) piperazine and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product obtained. A process according to claim 1 for the preparation of 1-3- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] propyl] -1,3-dihydro-2H-benzimidazol-2-one or the pharmaceutically acceptable acid addition salts thereof, characterized by reacting 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one methane sulfonate with 1- [bis (p-fluorophenyl) methyl] piperazine and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product obtained. A process according to claim 1 for the preparation of 1- [4- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] butyl] -1,3-dihydro-2H-benzimidazol-2-one or the pharmaceutically acceptable acid addition salts thereof, characterized by reacting 1- (4-chlorobutyl) -1,3-dihydro-2H-benzimidazol-2-one with 1- [bis (p-fluorophenyl) methyl] piperazine and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product obtained. DK 153477 B The process of claim 1 for the preparation of 1- [4- [4- (diphenylmethyl) -1-piperazinyl] butyl] -1,3-dihydro-2H-benz-imidazol-2-one or the pharmaceutically acceptable acid addition salts thereof, characterized by reacting 1- (4-chlorobutyl) -1,3-dihydro-2H-benzimidazol-2-one with 1- (diphenylmethyl) piperazine and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product obtained. Process according to claim 1 for the preparation of 1- [3- (4- (diphenylmethyl) -1-piperazinyl] propyl] -1H-benzimidazole or the pharmaceutically acceptable acid addition salts thereof, characterized by reacting 1- (3-chloropropyl) -1H-benzimidazole with 1- (diphenylmethyl) piperazine. Process according to claim 1 for the preparation of 1- [4- [4 - [(4-fluorophenyl) phenylmethyl] -1-piperazinyl] butyl] -1H-benzimidazole or the pharmaceutically acceptable acid addition salts thereof, characterized by reacting 1- (4-chlorobutyl) -1H-benzimidazole with 1 - [(4-fluorophenyl) phenylmethyl] piperazine and, if desired, produces a pharmaceutically acceptable acid addition salt of the product obtained. Process according to claim 1 for the preparation of 1- [4- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] butyl] -1H-benzimidazole or the pharmaceutically acceptable acid addition salts thereof, characterized in - (4-chlorobutyl) -1H-benzimidazole with 1- [bis (p-fluorophenyl) methyl] piperazine and, if desired, produces a pharmaceutically acceptable acid addition salt of the product obtained.