FI62667C - FOERFARANDE FOER FRAMSTAELLNING AV ANTIEMETISKA 1- (BENZAZOLYLALKYL) PIPERIDINDERIVAT - Google Patents

Description

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Patent · och registerstyrelaen v 'Amöktn uttagd oeh uti.skrMUn publiwrad 29.10.82 (32) (33) (31) Pnrfatty Vennootschap, Turnhoutsebaan 30,

Beerse, Belgium-Belgien (BE) (72) Jan Vandenberk, Beerse, Ludo E.J. Kennis, Vosselaar, Marcel J.M.C.

Van der Aa, Vosselaar, Albert H.M.Th. Vein Heertum, Vosselaar, Belgium-Belgien (BE) (TM Oy Kolster Ab (5 ^) Method for the preparation of anti-emetic 1- (benzazolylalkyl) piperidine derivatives - For the preparation of anti-emetic 1- (benzazolylic acid) piperidine derivatives

The invention relates to a process for the preparation of novel anti-emetic 1- (benzazolylalkyl) piperidine derivatives and their pharmaceutically acceptable acid addition salts. The formula for the new compounds is

i3 / “λ A

B N- (CH9) -CH- (CHO) “N j 'N NM (I) yi' m r1A = ^ Nr2 RlJk = ^ \ s 1 2 wherein R and R are hydrogen, halogen, lower alkyl or trifluoromethyl, B is a divalent -N (L) -CO- or -N = CH- radical attached to the benzene ring via a heteroatom, wherein L is hydrogen, lower alkyl, lower alkylcarbonyl or lower alkenyl, R is hydrogen or methyl, m 3a n represents an integer of 1 or 2, R and R represent hydrogen, 2,62667 halogen, lower alkyl or trifluoromethyl, Y is O or S, M is hydrogen, lower alkyl or lower alkylcarbonyl and the dashed line is a possible bond between carbon atoms 3 and 3 of the piperidine ring. 4, provided that when Y is S, there is a single bond between carbon atoms 3 and 4 of the piperidine ring and M is hydrogen.

Several benzazolylalkyl and indolylalkyl-substituted piperidine derivatives and several aminoalkyl-substituted benzazoles are known, some of which have pharmacological, e.g. antidepressant, anticonvulsant, antihistamine or antispasmogenic activity.

The compounds of the formula I differ from these known compounds, inter alia, in their chemical structure. The above-mentioned known compounds have been described e.g. in the following publications:

Int. Pharmacopsychiat. 1968 (1), pp. 214; C.A., 64, 2093 B (1966); C.A., 72, 111466 (1970); C.A., 81, 120632 b (1974); FR Patent 2,042,321 (Derw. Fr. Week S16, Pharma.

p. 12); and BE Patent 753,472.

U.S. Patent Nos. 3,161,645 and 3,238,216 describe compounds that are highly neuroleptic. Such compounds generally inhibit apomorphine-induced vomiting in dogs and this property is often considered a criterion for a possible neuroleptic effect. Although the compounds described in the above-mentioned patents have an antiemetic effect, they are not suitable for use as antiemetic agents because they are not specific. While having an antiemetic effect, they have a neuroleptic effect.

In contrast, the compounds of formula I are much more specific and the dose causing the antiemetic effect is much lower than that required to produce an effect on the central nervous system.

The term "lower alkyl" means a straight or branched chain alkyl having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl or pentyl. The term "lower 3 6 2 6 6 7 alkenyl" means a straight or branched chain alkenyl radical having 2 to 5 carbon atoms, such as, for example, 1-methylethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and and the term "halogen" means halogen having an atomic weight of less than 127, i. fluorine, chlorine, bromine and iodine.

Compounds of formula (I) and their pharmaceutically acceptable acid addition salts may be prepared by a) providing a compound of formula

B N— (CH ~) —CH— (CH_) —X

\ / 2 m 2 n f \ <«> 12 3 where R, R, R,. B, m and n are as defined above and X is a reactive ester group derived from the corresponding alcohol to react with a compound of formula

Y

II

HN;) - N n.-m \ y \ / (m) ä 7 8 wherein R, R, Y and M have the same meaning as above, in a suitable organic solvent, or b) the protecting group P is removed in a manner known per se in a compound of the formula S K3 »/ \ i ΓΛ / \

P-N N— (CH-) —CH— (CH-) —N, V_N N-M

<IV> r2 r7> C = Xr8 1 2 3 7 8 wherein R, R, R, R, R, m, n, Y and M have the same meaning as above, or 4 62667 c) cyclizing a compound of formula

r3 / A

H2? »<H- <CH2> m-CH- <ch2> n —f— \ / 'M

r \ M, v> r1 / C = ^ \ r2 R7 ^ “* \ 8 1 2 3 7 8 where R, R, R, R, R, m, n, Y and M have the same meaning as above, with the aid of a suitable cyclizing agent in a manner known per se, or d) cyclizing a compound of the formula / "" λ r3 / "v

\ y ‘CH2>„ - «=« - <CH2> n ”\ A

W NH / NH2 R ^ '-' \ s

R

1 2 3 7 8 wherein R, R, R, R, R, B, m and n are as defined above in a manner known per se using a suitable cyclizing agent, or e) N-alkylated or N-acylated in a manner known per se is an N-unsubstituted compound of the formula I a compound wherein Y is O by alkylation or acylation; and, if desired, converting the resulting compound of formula I into a pharmaceutically acceptable acid addition salt.

As a procedure, the condensation reaction according to option a) is preferably carried out in a suitable organic solvent, such as a lower alkanol, e.g. methanol, ethanol, propanol or butanol, or an aromatic hydrocarbon, e.g. benzene, methylbenzene or dimethylbenzene, or a ketone, e.g. 4-methyl In 2-pentanone or ether, e.g. 1,4-dioxane or 1,1'-oxybisethane, or N, N-dimethylformamide or nitrobenzene. A suitable base such as an alkali metal or alkaline earth metal carbonate or bicarbonate may be added to scavenge the acid liberated during the reaction. A small amount of metal iodide, e.g. sodium or potassium iodide, may be added to initiate the reaction, especially when the reactive ester of formula (II) is chloride. Somewhat elevated temperatures are appropriate to improve the reaction rate, and the reaction is preferably carried out at the reflux temperature of the reaction mixture. In this and other methods, the reaction products are separated from the medium and, if necessary, purified in a manner known per se.

In process variant b), the protecting group P is, for example, a lower alkyloxycarbonyl, 4-methylbenzenesulfonyl, methanesulfonyl, or a preferably substituted ethenyl group of the formula 1 2 R -CH = C-I11111211 wherein R and R may be different groups but R is cdulli - lower alkyl and R is preferably hydrogen, lower alkyl or phenyl.

When the protecting group is lower alkyloxycarbonyl, 4-methylbenzenesulfonyl or methanesulfonyl, it can be easily removed by alkaline hydrolysis, and when the protecting group is a substituted ethenyl group, it is removed by acid hydrolysis of intermediate (IV). In carrying out said acid hydrolysis to remove a substituted ethenyl group from intermediate (IV), a number of different protic acids can be used, such as mineral acids, e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid, or organic acids, e.g. acetic or propanoic acid. The reaction may be carried out in a reaction-inert organic solvent commonly used in this type of hydrolytic reaction, e.g. methanol, ethanol or 2-propanone.

The cyclizing agent used in process variant c) depends on the nature of the substituent B in the desired product.

The cyclization reaction can be carried out using methods known per se for the preparation of 1H-benzimidazoles and 1,3-dihydro-2H-benzimidazol-2-ones starting from 1,2-benzenediamines. Suitable cyclizing agents which can be advantageously used for the preparation of compounds of formula I in which B is -NH-C (O) - include, for example, urea, carbonyl dichloride and alkali metal isocyanates. For example, when urea is used as a cyclizing agent, the desired compounds are obtained by stirring and heating the reaction component 6 62 667 together without a solvent.

When B in the compounds of formula I is -N = CH-, formic acid or tri (alkyloxy) methane can be used as the cyclizing agent.

In the cyclization reaction according to process variant d), the same cyclizing agents as described above can be used.

In process variant e) N-alkylation can be carried out e.g. by reacting an unsubstituted compound with a suitable reactive ester derived from a suitable lower alkanol, e.g. halogen-lower alkane or lower alkyl methanesulfonate or 4-methylbenzenesulfonate in the same conditions as above described in method option a). The acylation can be carried out by reacting an unsubstituted compound with an anhydride or an acyl halide derived from a suitable lower alkylcarboxylic acid using N-acylation methods known per se.

When B in the compounds of formula I is -NH-C (O) -, it is suitable to start from a compound of formula 0 R3 12 Λ i / - \ / H ° r "W 2 m 2" Y _ /% m

A *, H

R R (IV-a) R 7 is substituted by N-alkylation or N-acylation as described above, after which the substituted ethenyl protecting group is removed by acid hydrolysis.

Compounds of formula I wherein B is -N (L) -C (O) -, wherein L is a lower alkyl or lower alkylcarbonyl radical identical to M, may be further prepared starting from the appropriate compound of formula I. wherein B is -NH-CO- (L = H), M is hydrogen and Y is O, by alkylation or acylation of both 1H-Benzimidazole groups in one reaction step.

The starting materials used in the methods described above are obtained as follows. Reactive esters of formula (II) wherein B is -NH-CO- (L = H) or -N = CH may be prepared by reacting an appropriately substituted 2-chloronitrobenzene of formula (VIII) with the appropriate aminoalkanol (IX) under heating. - 7 62 6 67 rows of the reaction components while refluxing in an inert organic solvent such as a lower alkanol, e.g. ethanol, 2-propanol or butanol, followed by reduction of the / * (2-nitrophenyl) amino] alkanol of formula (X) to give the nitro group, e.g. by catalytic hydrogenation using a Raney nickel catalyst. The / '(2-aminophenyl) amino] alkanol of formula (XI) thus obtained is then reacted with a suitable cyclizing agent described above in connection with process variant c) and the alcohol of formula (XII) thus obtained is then converted to the desired compound of formula (II-a). reactive ester in a manner known per se.

The halides are conveniently prepared by reacting a compound of formula (XII) with a suitable halogenating agent such as sulfinyl chloride, sulphyryl chloride, phosphorus pentachloride, phosphorus pentabromide or phosphoryl chloride. When the reactive ester is iodide, it is preferably obtained 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 an alcohol with a suitable sulfonyl halide such as methanesulfonyl chloride and 4-methylbenzenesulfonyl chloride.

The above reactions can be more clearly described by the following reaction scheme: ° 2V / f3 * H2N- (CH2) m-CH- (CH2) n-OH -> rI ^ ^ R2 (IX) (VIII) R3

00N NH- (CHO) -yl · - (CHO) -OH

2 v, 2 m 2 n H VRaNi R (X) 8 62 66 7

Η_Ν ΝΉ- (CH ~) -CH- (CH 2) -OH

2 T 2. m 2 n / \ ring closure R1 r2 (XI) r ~ \

B N- (CH2) -CH- (CH2) -OH

formation of reactive ester F ^ (II-a) r1 - ^ \ === / ^ r2 (XII)

Intermediates of formula (II) wherein B is -N (17) -C0- or -N = CH-, wherein 17 is lower alkyl, lower alkenyl or lower alkylcarbonyl, may be prepared by coupling a reactive ester side chain in a manner known per se. to a compound of formula

B

\ (XIII)

For example, a hydroxy alkyl chain can be attached by N-alkylating a compound of formula (XIII) with a haloalkanol of formula (XIV) to give an alcohol of formula (XV), the hydroxyl group of which is then converted to a reactive ester group in a manner known per se. Instead of a haloalkanol of formula (XIV), its tetrahydro-2H-pyran-2-yl ether derivative can also be used to give the corresponding ether derivative, the ether group of which is opened by acid hydrolysis, e.g. by stirring and heating the ether compound in dilute hydrochloric acid.

When the reactive ester of formula (ΙΙ-b) is a halide (II-b-1), it may alternatively be prepared by reacting a compound of formula (XIII) with an equivalent of the appropriate dihaloalkane of formula (XVI) to give a strong base. such as in the presence of sodium methanolate or following the Mackosza process using an aqueous alkali and quaternary ammonium catalyst, e.g., Ν, Ν, Ν-triethylbenzenemethanamine chloride.

The above process can be described as follows: R3 (XIII) + halo- (CH2) m-CH- (CH2) n-OH N-alkylation ______> (XIV) S- (CH_) -CH- (CH5) -OH reactive ether dostus _______ ^ (11 - b) o (XV)

k R

R3 (XIII) + halo- (CHO) -CH- (CHn) -halo base \ 2 m 2 n —---------,) ^ f <CH2> m-CH_ (CH2> n-hal ° and, RR (II-b-1)

Intermediates of formula II wherein B is -NH-CO- (L = H) can be prepared by attaching a reactive ester side chain to a compound of formula 0

B

P- ^ \ h / \ (XVII) R2 wherein P is a protecting group as defined above, and subsequently deprotecting the compound of formula XIX thus obtained in a manner known per se as described above. Reactive ester side chain coupling can be performed in the same manner as described above for coupling of the side chain to starting materials of formula (XIII). For example, hydroxy-10 6? The alkyl chain is then reacted to give the hydroxyl group of the intermediate of formula (XVIII) thus obtained. as an ester group to obtain a compound of formula (XIX), or when the reactive ester is a halide (ΧΙΧ-a) said halide can be obtained directly by reacting a compound of formula (XVII) with a dihaloalkane. When the protecting group P is to be subjected to alkaline hydrolysis, e.g. being lower alkyloxycarbonyl, methanesulphonyl or 4-methylbenzenesulphonyl, the N-alkylation reaction to attach the corresponding hydroxyalkyl or haloalkyl chain must be carried out under non-hydrolytic conditions, e.g. e.g. sodium hydride or sodium methanolate in a suitable aprotic organic solvent such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide or hexamethylphosphoric triamide.

The reactions described above can be more clearly illustrated by the following reaction scheme: 0 3 C,

(XVII) + (XIV) ™ lkyl01 P-t / \ - (CHO) -CH- (CHO) -OH

nen_ V i 2 m 2 n jrt a + (XVI) R1 ^ Λι ====? \ J / (XVIII) reactive ester formation 0 0 "3 ^ f S '^ R3 PN N- (CH ~) -CH- (CH_) -halo PN ^ VlCHJ -CH- (CH0) -X \ / zm 2 nv 7 2m 2n Ä .A, (XIX) (ΧΙΧ-a) „.

, n _ P removal vJ / P removal r O 3 C. Φ HN1 ^ (CH2) m "CH- (CH2) -halo (II-c) rJLxr2 (II-C-1) 11 6 2 6 6 7 2

Intermediates of formula II wherein B is -N (L) -CO-, 2 wherein L is lower alkyl or lower alkenyl in which the unsaturated L is in the β 3 or S position can be prepared as follows.

An intermediate of formula (II-c) wherein m and n are each 1, (II-c-2) is treated with sodium metal in absolute ethanol to form a cyclic ether of formula (XX). It is then reacted with a reactive ester LX, of formula 2 2 (XXI) wherein L and X are as defined above, e.g. by heating the reaction component under reflux in an organic solvent such as 2-propanone to give the desired intermediate (II-). d).

A rWO

h [Q-ch2-ch_ch2x abso; a .essn »/ \ (XX) R1> ^ R2 (II-c-2) 2 / C \ f - 4 l2-n \ -ch ^ -ch-ch_-x (XXD V / 2 2 R 2 ^ NR (II-d)

Compounds of formula (IV) used as intermediates in process variant b) can be obtained by condensing an intermediate of formula (XIX) with an intermediate of formula (III) under conditions similar to those described above for the preparation of compounds of formula I from starting materials (II) and (III). ).

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

Intermediates of formula (IV) in which there is a single bond between carbon atoms 3 and 4 of the pyridine ring and M is hydrogen (IV-b) can be prepared by condensing a reactive ester of formula (XIX) with N- (2- nitrophenyl) -4-piperidinamine followed by reduction of the nitro group of the compound of formula (XXIII) thus obtained by a reduction method known per se to reduce the nitro group to the amine group, e.g. by reacting the nitro compound with liberated hydrogen or hydrogenating obtained benzenediamine (XXIV) with the cyclizing agent described above.

The reactions described above can be represented by the following reaction scheme: (XIX) + HN v N_ / 'NH NO 2' 7? r3 C ** f '"" "V v

P-N is N- (CH-) -CH- (CH9) -NX

2 m W \ y «o2 r1A-K2 ρ> ^ \ ρβ

(XXIII) K

0 3 _ £? α-Λ, η

to nitroamine y P-N N-ICH2> m-c «-« CH2> η "ΝΝ __ / ^ ΝΗ NH

reduction / Λ M

rV ^ Cs = Xr2 r7 ^ \ = Ar8 (XXIV) cyclization (IV-b) 13 6 2 6 6 7

The starting materials of formula (XXII) can be prepared by the method described in U.S. Patent 3,910,930.

Intermediates of formula (V) are obtained by condensation of a reactive ester of formula (XXV) with a piperidine derivative of formula (III) followed by reduction of the nitro group of the intermediate of formula (XXVI) thus obtained to an amino group by a reduction method known per se.

R3 00N NH- (CH_) -CH- (CHO) -X + (III) -) 2 \ J 2 m 2 n Ä R (XXV)

Y

3 "* / c \ 0NN NH- (CH, J_-CH- (CH.J -N> -N NM to nitroamine x (V) 2W 2 m 2 n \ -J \ J reduction - ^ Ä Ä · (XXVI)

The reactive ester of formula (XXV) used as a starting material is readily prepared starting from the alcohol of formula (X) by converting its hydroxyl group to a reactive ester group as described above.

An intermediate of formula (VI) can be prepared by condensing a reactive ester of formula (II) with an N- (2-nitrophenyl) -4-piperidinamine of formula (XXII) and then reducing the nitro group of the compound (XXVII) thus obtained to an amine group by a reduction method known per se. which is also described above.

It should be noted that when the reduction of a nitro group to an amine group is carried out by catalytic hydrogenation using a palladium on carbon catalyst, dehalogenation of compounds in the presence of aromatic halogen substituents can occur.

14 62 6 67 f / - \ /

(II) + (XXII) -> B / N "(CH2) m" CH_ (CH2) n ~ N \ X

Vi Ψ / ° 2 r1 τ 'N 8

(XXVII) R R

reduction to the nitroamine

The starting materials of formula (III) wherein Y is 0 can be prepared by the methods described in U.S. Pat. No. 3,161,645 and BE-830,403.

The starting materials of formula (III) wherein Y is S can be prepared by cyclization of N- (2-aminophenyl) -4-piperidinamine of the formula ° ΛΛ / Η

(lower alkyl) O-C-ttf Y

NH NH2 (xxix) f, 5 r7 ^ === N8 with a cyclizing agent, e.g. carbon disulphide and then removing the lower alkyloxycarbonyl group of the compound (XXX) thus obtained by alkaline hydrolysis.

N- (2-aminophenyl) -4-piperidinamines of formula (XXIX), several of which are known compounds, can be prepared by the methods described in U.S. Patent Nos. 3,910,930 and BE-830,403.

15 62 667 (XXIX) cyclization> '

π / - \ yH S

(lower alkyl) O-C-N V E-QH j (III, Y-S)

'-'n NH

The other starting materials used are either known or can be prepared according to analogous methods known per se.

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

Such compounds are especially prepared by reacting an ester of formula (XXXII) wherein R and R are as defined above with a benzenediamine of formula (XXXIII). Said reaction is preferably carried out by stirring and heating the reaction components under reflux in an inert organic solvent while azeotropically removing water. Suitable inert organic solvents for this purpose include, for example, aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene and the like.

0 R 1 -CH-C-O- (lower alkyl) + HNN NHO 1 (__ / -> i ~ sn lxxxII) (XXXIII) 16 6 2 6 t> 7 o R 12 -CH = C - R1] ^ (XVII-a) R R2

The intermediates of formulas (V) and (VI) are novel compounds.

The compounds of formula I may be converted into therapeutically useful acid addition salts by treatment with a suitable acid, e.g. an inorganic acid such as hydrohalic acid, e.g. hydrochloric, hydrobromic and the like; or sulfuric acid, nitric acid, phosphoric acid and the like; or an organic acid such as acetic, propane, hydroxyacetic, 2-hydroxypropane, 2-oxopropane, propanediol, carboxylic, butanedicarboxylic, (Z) -2-butenedicarboxylic, (E) -2-butenedicarboxylic, 2-hydroxybutanedicarboxylic, 2,3-dihydroxybutanedicarboxylic, 1-, 2-hydroxy-1,2,3-propanetricarboxylic, benzoic, 3-phenyl-2-propenecarboxylic, hydroxybenzeneacetic, methanesulfonic, ethanesulfonic , benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamine, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. The salt form can also be converted to the free base form by treatment with an alkali.

The compounds of formula (I) and their therapeutically active acid addition salts have a strong antiemetic (antiemetic) effect, as demonstrated by their ability to inhibit apomorphine-induced emesis in dogs. The research method used has been 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, followed 1 hour later by a standard dose of 0.31 mg / kg (subcutaneously) apomorphine.

The following tables show the ED 2 Q values of some of the compounds of formula (I). The ED 2 value then means a dose that protects 50% of the animals against vomiting.

17

Table I 62667

O „3 O

11 i f— \) - ^ JL-N -Clk-Cll-Cll -N> 411 \ / 2 2 \ _ /

M M

1? '7 K1 K n

__ Salt and soi IIP

1 -, 2 „3. {\ Ti ^ wattage form -Ό L R R K ^ K m [', /); f; p.

HHHH 11 - ° · 02 H 5-Cl HH "M - 0.10 H 5-CH 6-CH3 H" H CH3-CHOH-CH3 0.45 HHH CH3 "5-C1 - 0.06 Π HHH" 5-C1 - 0.01 H 5- C1 HH "5-C1 - 0.12

CH H H H "5-Cl - 0.) G

3H -CH-CH 1 HHH "5-Cl - 0.12 j HHHH tQ) H - 0.04 H 5 -FHH isQ 5 - Cl HCl H?. ° 0.004 H 5-CH 3, HH 5-Cl HCl H 2 O 0.12 C (CH 2) = CH2 h HH "5 -Cl - 0.20 H 5-CH3 HH" H MCI K2O 0.20 18 6 2 6 h 7

Table II____

Compound ED50 m9 / kg s.c.

8 / - \ 11 ς

HN ^ 'N-ICL! ), -N X

W Z 3 \ _ / N, N11

o X

O, H '- 7 HN ^ N- (CH) -N / jX 0.004

ÖZ 3 \ _ / 'n "NM

ö

Cl

Table III compares the specific antiemetic activity of domperidone of formula I with that of known compounds. Dogs were subjected to an antiapomorphine test (A) to determine the quantitative antiemetic effect and to determine the quantitative CNS depressant effect (B). These experiments are described in Arzneim.-Forsch.

(Drug Research), J_3, 205 (1963).

Table III

Compound A B Specific emetic

EDca Anti-EDCrt effect A / B

DU DU

------—_ domperidone 0.90 0.003 300 (compound of formula I) spiperone 0.0047 0.000260 18 (known) benperidol3 0.0040 0.00050 8 (known) droperidol ^ 0.0080 0 , 0012 6.7 (known) _________ 62667 19 0 o / \ / - /% 1) HN N-CH2-CH2-CH2-N VL / \ h

o H

^ ci 2) F - ^> ^ - ch2-ch2-ch2-n (3> Jh (US 3 238 216) ^ j) 3) F ^ ^ ^ C-CH2-CH2-CH2-f ^) ^ H 2 ( U.S. 3,161,645) Yh

O

o 0 4) F — f \ —C — CH0-CH0-CH „-N V— \ = y 2 2 2 YV“ y? 11 (US 3,161,645) f \

Due to their useful antiemetic activity, the compounds of formula (I) may be formulated into various pharmaceutical forms for administration. To prepare pharmaceutical compositions, an antiemetic effective amount of the compound in the form of either a base or an acid addition salt is mixed with a pharmaceutically acceptable carrier, the choice of which depends on the formulation desired for administration. These pharmaceutical compositions are preferably in unit dosage form suitable for oral or rectal administration or for parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, e.g., water, glycols, oils, alcohols, and the like, such as suspensions, syrups, elixirs, and solutions. Useful solid carriers include starches, sugars, kaolin, lubricants. In addition, binders, disintegrants, and the like can be used with powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at which point the carrier may be saline, glucose, or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case liquid carriers, suspending agents and the like may be employed. Acid addition salts of the compounds due to their higher water solubility over the base form are often preferred in the preparation of aqueous compositions.

It is preferable to formulate the aforementioned pharmaceutical compositions in dosage unit form for simplification and uniformity of dosage. Unit dosage form thus means physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient to produce the desired therapeutic effect in association with the pharmaceutical carrier. Examples of such dosage unit forms are tablets, capsules, pills, powder packets, injectable solutions or suspensions, and the like.

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

The following examples illustrate the invention. All parts are by weight unless otherwise indicated.

Preparation of starting materials

Example I

A mixture of 100 parts of 1-chloro-2-nitro-4- (trifluoromethyl) benzene, 90 parts of 3-amino-1-propanol and 200 parts of butanol is stirred and refluxed. Stirring is continued overnight. The reaction mixture is cooled and evaporated. Water is added to the residue and acidified with hydrochloric acid solution. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The solid residue is crystallized from petroleum ether. The product is filtered off and dried, yielding 141 parts (100%) of 3 - (/ 2-nitro-4- (trifluoromethyl) phenyl / amino) -1-propanol.

Example II

According to Example I and using equivalent amounts of the corresponding 21 ο ζ ο 6 / starting materials are prepared: 3 - [(4-methyl-2-nitrophenyl) amino] -1-propanol as a residue; 3- (η 5 -dichloro-2-nitrophenyl) amino] -1-propanol, m.p. 97 ° C; and 3- [2- (2-chloro-6-nitrophenyl) amino] -1,7-propanol as a residue.

Example III

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

Example IV

A mixture of 141 parts of 3- (R) -nitro-4- (trifluoromethyl) -

> N

phenylamino) -1-propanol and 1200 parts of methanol, hydrogenated under normal pressure and at room temperature using 15 parts of Raney-Nikke diluent catalyst. After the calculated amount of hydrogen has been consumed, 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- (1,2-amino-4- (trifluoromethyl) phenyl) amino] -1-propanol.

Example V

Following the procedure of Example IV and using equivalent amounts of the corresponding starting materials, the following are prepared: 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.

Example VI

To a stirred and cooled solution of 54 parts of 3 - [(2-amino-4-methylphenyl) amino] -1-1-propanol in 30 parts of chlorohydric acid solution (10%) and 200 parts of water is added dropwise a solution of 28 parts of potassium cyanate in 50 parts of water at a temperature below 10 ° C. After the addition is complete, stirring is continued first for 1 hour at room temperature and then for 24 hours at reflux temperature. After cooling to room temperature, the product is extracted with trichloromethane. The extract is washed with hydrochloric acid solution (5%), dried, filtered and evaporated. The residue is crystallized from 22,62667 4-methyl-2-pentanone to give 19.5 parts (31%) of 1,3-dihydro-1- (3-hydroxypropyl) -5-methyl-2H-benzimidate sol. i-2-one, m.p. 114.1 ° C.

Example VII

Following the procedure of Example VI and using equivalent amounts of the corresponding starting materials, the following is prepared: 1,3-dihydro-1- (3-hydroxypropyl) -5- (trifluoromethyl) -2H-benzimidazol-2-one; 5,6-dichloro-1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one; mp. 174.7 ° C; 4-chloro-1,3-dihydro-3- (3-hydroxypropyl) -2H-benzimidazol-2-one; and 5-chloro-1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one; mp. 148.8 ° C.

Example VIII

To a stirred solution of 18.5 parts of 1,3-dihydro-1- (3-hydroxypropyl) -5-methyl-2H-benzimidazol-2-one and 32 parts of dichloromethane is added 11.9 parts of part of N, N-diethylethanamine. 11.5 parts of methanesulfonyl chloride are added dropwise (slowly). After the addition is complete, 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 IX

Following the procedure of Example VIII and using equivalent amounts of the corresponding starting materials, the following is prepared: 3- (5,6-dichloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -propyl methanesulfonate as an oily residue; 3- (7-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl methanesulfonate; and 3- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl methanesulfonate; mp. + 140 ° C.

23 62 6 6 7

Example X

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 refluxed overnight. The reaction mixture is cooled to room temperature, filtered and the filtrate is evaporated. The residue is stirred in water and acidified with dilute hydrochloric acid solution. It is then 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 basified with ammonium hydroxide. The product is extracted with dichloromethane. The product is dried, filtered and evaporated to give 50 parts of ΙΗ-benzimidazole-1-butanol as an oily residue.

Example XI

To a stirred mixture of 23 parts of 1,3-dihydro-1- (3-hydroxypropyl) -5- (trifluoromethyl) -2H-benzimidazol-2-one in 150 parts of trichloromethane is added dropwise 32 parts of sulfinyl chloride. At the end of the addition, heat 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 -uni a.

Example XII

Following the procedure of Example XI and using an equivalent amount of the corresponding 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; mp. 122 ° C; and 1- (4-chlorobutyl) -1H-benzimidazole as an oily residue.

Example XIII

To a stirred and refluxed mixture of 35 parts of 4-fluoro-1,2-benzenediamine in 270 parts of dimethylbenzene is added dropwise over 2 hours a solution of 57 parts of ethyl-N-acetylbenzene acetate in 90 parts of dimethylbenzene, while forming distilled off (water separator).

24 62667

The reaction mixture is evaporated and the residue is crystallized from 2-propanol.

The product is filtered and purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 11 parts of 6-fluoro-1,3-dihydro-1- (1-methyl-2-phenylethenyl) -2H-benzimidazol-2-one, m.p. 190 ° C.

Example XIV

To a stirred solution of 8.5 parts of 1,3-dihydro-1- (1-methylethenyl) -2H-benzimidazol-2-one in 45 parts of N, N-dimethylformamide is added portionwise 1.7 parts of sodium hydride dispersion ( 78%). After stirring for 1 hour at room temperature, cool to 0-5 ° C and drop dropwise or n (slowly) 8.65 parts of 1-bromo-3-chloropropane. After the addition is complete, stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto crushed ice and the product is extracted with methylbenzene.

The extract is washed with water, dried, filtered and evaporated. The 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 XV

To a stirred and hot (55 ° C) mixture of 22.2 parts of 1,3-dihydro-5,6-dimethyl-3- (1-methyl-2-phenylethenyl) -2H-benzimidazol-2-one, 3 parts of Ν, Ν, Ν-triethylbenzenemethanamine ammonium chloride and 112.5 parts of sodium hydroxide solution (60%) are added dropwise 15.8 parts of 1-bromo-3-chloropropane (slightly exothermic reaction). After the addition is complete, 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 (8.5%) of 1- (3-chloropropyl) -1,3-dihydro-5,6-dimethyl-3- (1-methyl-2- phenylethenyl) -2H-benzimidazol-2-one, m.p. 98 ° C.

Example XVI

Following the procedure of Example XV and using equivalent amounts of the corresponding starting materials are prepared: 1- (3-chloropropyl) -1,3-dihydro-3- (2-propenyl) -2H-benzimidazol-2-one as a residue; 62667 25 1- (3-chloro-2-methylpropyl) -1,3-dihydro-3- (1-methyletonyl) -211-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 XVII

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

Example XVIII

A mixture of 25 parts of 1- (3-chloropropyl) -1,3-dihydro-5,6-dimethyl-3- (1-methyl-2-phenylethenyl) -2H-benzimidazol-2-one, 165 parts of 6N hydrochloric acid solution and 160 parts of ethanol, are stirred and refluxed for 6 hours. The reaction mixture is evaporated and the residue is dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybis-propane and 2-propanol to give, after drying, 16 parts (94.7%) of 1- (3-chloropropyl) -1,3-dihydro-5,6-dimethyl-2H -benzimidazol-2-one, m.p. 140 ° C.

Example XIX

A solution of 180 parts of 3 - [(2-nitrophenylamino) -1-propanol in 200 parts of methanol and 100 parts of 10N hydrochloric acid solution is hydrogenated under normal pressure and at 50 ° C in the presence of 5 parts of palladium on carbon (10%). After the calculated amount of hydrogen (3 moles) has elapsed, the hydrogenation is stopped, the catalyst is filtered off and the filtrate is evaporated, and the residue (mainly 3- (2-amino-phenyl) amino] -1-propanol hydrochloride) is dissolved in 500 parts of water. a solution of 88.8 parts of potassium isocyanate in 150 parts of water is stirred and refluxed 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 carbon and crystallized at room temperature. The precipitate is filtered off and recrystallized from 400 parts of water and then from ethyl acetate to give 58 parts of 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzene. imidazol-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 air for 2 hours. The pyridine is evaporated. 500 parts of water are added to the residue and the precipitate formed is filtered off. It is dissolved in 350 parts of trichloromethane. The resulting solution is dried over magnesium sulfate and evaporated. The residue is crystallized from M-0 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. Stir into the roll until all solids are dissolved. The solution is further stirred and refluxed for 2 hours. After cooling, the reaction mixture is filtered off with small amounts of inorganic matter and the filtrate is evaporated. The residue is dissolved in 80 parts of methylbenzene, boiled with activated carbon, 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-1,3,3-oxazino-3,2-α-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 stirred and refluxed for 2 hours 50 minutes. . A second portion of 5.7 parts of iodomethane is added and the mixture is further stirred and refluxed for 2 hours and 50 minutes. The solvent is evaporated to give 1,3-dihydro-1- (3-iodopropyl) -3-methyl-2H-benzimidazol-2-one as an oily residue.

Example XX

A mixture of 84 parts of ethyl 4- (4- (4-chloro-2-nitrophenyl) -amino] -piperidinecarboxylate and 750 parts of a solution of hydrobromic acid (48%) in water is stirred and refluxed for H 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 hydrobromide, m.p. 275 ° C.

A mixture of 105 parts of 1- (3-chloropropyl) -1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazol-2-one, 71 parts of N- (4-chloro-2-one) -nitrophenyl) -4-piperidinamine hydrobromide, 53 parts of sodium carbonate, 0.2 parts of potassium iodide and 320 parts of 4-methyl-2-pentanone, are stirred and refluxed for 24 hours using a water separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated, yielding 98.5 parts (100%) of 1- [3- (4- (4-chloro-2-nitrophenyl) amino] -1-piperidinyl) propyl. -dihydro-2- (1-methylethenyl) -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- methylethyl) -2H-benzimidazol-2-one in 360 parts of methylbenzene, is acidified with 2-propanol pre-saturated with gaseous hydrogen chloride. After boiling, oil precipitates. The upper phase is decanted off and the remaining oil is suspended in water. The suspension is basified with concentrated ammonium hydroxide solution. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 68 parts (75.5%) of 1- [3- (4- (~ (4-chloro-2-nitrophenyl) amino] -1-piperidinyl) propyl? -l, 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-benzene : im: da zol i-2-one and 240 parts of methanol are hydrogenated at normal pressure at room temperature using 5 parts of Raney nickel catalyst. After the calculated amount of hydrogen has been consumed, 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 ) propyl-1,3-dihydro-2H-benzimidazol-2-one as a residue.

Example XXI

A mixture of 21.5 parts of 1- [3- (4 - [(4-chloro-2-nitrophenyl) amino] -1-piperidinyl) propyl] -1,3-dihydro-2H-benzimidazolicon and 240 parts methanol, is hydrogenated at normal pressure using 10 parts of palladium on carbon (10%). After the calculated amount of hydrogen has been consumed, 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.

Example XXII

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: temperature rises to 45 ° C). After the addition is complete, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated to give 43 parts (100%) of N- (3-chloropropyl) -2-nitrobenzeneamine as a residue.

A mixture of 43 parts of N- (3-chloropropyl) -2-nitrobenzeneamine, 47.8 parts of 5-chloro-1,3-dihydro-1- (4-piperidinyl) -2H-benzimidazol-2-one, 30.3 parts of N, N-diethylethanamine and 180 parts of N, N-dimethylacetamide are stirred and heated at 100 ° C for 6 hours. The reaction mixture is cooled and poured into 1500 parts of water. The precipitated product is filtered off, washed with water and dried over 2,2'-oxybispropane to give 64 parts (78.3%) of 5-chloro-1,3-dihydro-1- (1- {3- (2- ? nitrophenylamino) -propyl -4-piperidinyl) -2H-benzimidazol-2-one; mp. 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 , is hydrogenated at normal pressure at room temperature using 10 parts of Raney-Nikke dirt catalyst. After the calculated amount of hydrogen has been consumed, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from a mixture of 2-propanol and ethanol. The product is filtered off and dried, yielding 42 parts (70.5%) of 1- (3- [N- (2-aminophenyl) amino] propyl) -4-piperidinyl) -5-chloro-1,5-dihydro-1H- benzimidazole ^ -one; mp. 196 ° C.

62667 29

Manufacture of finished products

Example 1 5-Chloro-1- (1- [3- (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) propyl] -4-piperidinyl) -1,3-dihydro-2H-benzimidazole 2-one.

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-pipe -ridinyl) -2H-benzimidazol-2-one, 3.2 parts of sodium carbonate, 0.1 part of potassium iodine and 80 parts of 4-methyl-2-pentanone, are stirred and refluxed for 24 hours. The reaction mixture is cooled to room temperature and water is added. The insoluble matter is filtered off and purified by column chromatography on silica gel using trichloromethane with 10% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered and recrystallized from a mixture of Ν, Ν-dimethylformamide and water to give 1.3 parts (30%) of 5-chloro-1- (1- / 3- (1,3-dihydro-2-oxo-2H-benzimidazole). -1-yl) propyl-4-piperidinyl) -1,3-dihydro-2H-benzimidazole-2-one; mp. 242.5 ° C.

As described above, using an equivalent amount of the corresponding starting materials, the following compounds were prepared: 5-chloro-1- [1- (3- / 5,3-dihydro-3- (1-methylethenyl) -2-oxo-1H-benzimidazol-1-yl] 2-methylpropyl) -4-piperidinyl-1,3-dihydro-2H-benzimidazol-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-one hydrate thereof; mp. 179.6 ° C; 1- (3- / 4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl) -1,3-dohydro-5,6-dimethyl-2H -benzimidazol-2-one 2-propanolate; mp. 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 ; mp. 273 ° C; 1- (3 - ^ - (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidin-nyyli7-propyl) -1,3-dihydro-2H-benzimidazol-2-one; mp. 225 ° C; 1,3-dihydro-1- (3- / 4- (2,3-dohydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl) -5- (trifluoromethyl) -2H-benzimidazol-2 -one; mp. 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 ; mp. 253-255 ° C; 30,62667 5-Chloro-1 / 1- (3- [2,3-dihydro-2-oxo-3- (2-propylene) -1H-benzimidazol-1-yl] propyl) -4-piperidinyl] ~ 1,3-dihydro-2H-benzimidazol-2-one; mp. 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-bentsimidatso1-2-one; mp. 206.6 ° C; 5-Chloro-1- [1- (3-72,3-dihydro-3- (1-methylethenyl) -2-oxo-1H-benzimidazol-1-yl] propyl) -4-piperidinyl] -1,3,3 dihydro-2H-benz-imidazol-2-one; mp. 165.2 ° C; 1- (1- / 4- (1H-benzimidazol-1-yl) butyyli7-4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one; mp. 157.1 ° C.

1- (3- / 4- (5,6-dichloro-1,3-dohydro-2-oxo-2H-benzimidazol-1-yl) -1-piperidinyl / propyl) -1,3-dihydro-2H-benzimidazole -2-one; mp: 263.1 ° C.

5-Bromo-1- (3- / 4- (5-chloro-1,3-dihydro-1-oxo-2H-benzimidazol-1-yl) -1-piperidinyl] propyl) -1,3-dihydro-2H-benzimidazole - 2-one; mp: 255.6 ° C / H-2-butenedicarboxylate (1: 1) _7? and 1- (3 - ["4- {5-bromo-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) -1-piperidinyl / propyl) -1,3-dihydro- 2H-benzimidazol-2-one, mp 292.3 ° C (HCl. H 2 O).

Example 2 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.

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 of sodium carbonate and 200 parts of 4-methyl-2-pentanone are stirred and heated under ball cooling overnight using a water separator. After cooling, water is added and the layers are separated. The 4-methyl-2-pentanone phase is dried, filtered and evaporated.

the oily residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 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.

As described above, using equivalent amounts of 3i 62. 6 6 7 of the corresponding starting materials, the following compounds were prepared: 1- (3 - [- (5-chloro-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; 3- (3- [4 - (- 5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl) -1,3-dihydro-5-methyl- 1- (1-methylethenyl) -2H-benzimidazol-2-one as an oily residue; 1- (1- [3- (1H-benzimidazol-1-yl) propyl] -4-piperidinyl) -5-chloro-1,3-dihydro-2H-benzimidazol-2-one, m.p. 224 ° C, and 1- [1- [3- (1H-benzimidazol-1-yl) propyl] -4-piperidinyl] -1H-3-dihydro-2H-benzimidazol-2-one dihydrochloride hydrate, m.p. 292.1 ° C.

Example 3 5-Chloro-1- (1- [3- (1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl) propyl] -4-piperidinyl) -1,3-dihydro- 2H-benzimidazol-2-one.

A mixture of 5 parts of 1,3-dihydro-1- (3-iodopropyl) -3-methyl-2H-benzimidazol-2-one, 3.75 parts of 5-chloro-1,3-dihydro-1- (4- piperidinyl) -2H-benzimidazol-2-one, 2.65 parts of sodium carbonate and 22.5 parts of Ν, Ν-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- / 3- (1,3-dihydro-3-methyl-2-oxo-2H-benzomidazole-1). -yl) propyl-4- (piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one; mp. 166.5 ° C.

Example 4 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

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 of sodium carbonate and 63 parts of Ν, 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, eluting with trichloromethane containing 10% methanol.

The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized from a mixture of Ν, Ν-dimethylformamide and water. It is filtered again and dissolved in a small mixture of 4-methyl-2-pentanone and onin, Ν-dimethylformamide.

The solution is filtered clear and the filtrate is concentrated to a volume of about 10 parts. The concentrate is mixed with methanol. The precipitated product is filtered off and dried, yielding 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-benzimidazole-2-one; mp. 229-236 ° C.

Example 5 1- (3- / 4- (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.

A mixture of 7 parts of 1- (3-chloropropyl) -5-fluoro-1,3-dihydro-3- (1-methyl) -2-phenylethenyl) -2H-benzimidazol-2-one, 5 parts of 5-chloro -1,3-dihydro-1- (4-piperidinyl) -2H-benzimidazol-2-one, 4.25 parts of sodium carbonate, 0.1 part of potassium iodine and 200 parts of 4-methyl-2-pentanone, are stirred and refluxed. overnight. 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 refluxed overnight with a solution of 55 parts of a 6N hydrochloric acid solution in 40 parts of ethanol. The solvent is evaporated off and the residue is taken up in water. It is then basified 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 into the hydrochloric acid salt in 2-propanol. The salt is filtered off and dried, yielding 1.2 parts of 1- (3- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl) - 5-fluoro-1,3-dihydro-2H-benzimidazole-2-one hydrochloride hydrate; mp. 250 ° C.

As described above, the following were prepared: 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; mp. 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; 62667 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; mp. 174.3 ° C, by reacting 1- (3-chloropropyl) 1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazol-2-one with 1- (1-methylethyl) -3- (4-piperidinyl ) -2H-benzimidazol-2-one.

Example 6 1- (3- [3- (2,3-Dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl) -1,3-dihydro-5-methyl-2H-benzimidazole -2-one-hydro-chloride hydrate thereof.

Mixture of 6 parts of 1- (3- / 4- (2,3-dihydro-2-oxo-11-benzimidazol-1-yl) -1-piperidinyl] propyl) -1,3-dihydro-5-methyl-3 - (1-methylethenyl) -2H-benzimidazol-2-one, 12 parts of hydrochloric acid solution, 30 parts of water and 40 parts of ethanol are stirred first at 50 ° C and then 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, yielding 3.7 parts (40%) of 1- (3- / 4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl) -1, 3-dihydro-5-methyl-2H-benzimidazole-2-one hydrochloride hydrate; sp.251,4 ° C.

As described above, the following compounds were prepared from the corresponding (1-methylethenyl) substituted analogs: 5-Chloro-1- (1- [3- (2,3-dihydro-5-methyl-2-oxo-1H-benzimidazol-1-yl)] (P-p-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one hydrochloride, mp 213.3 ° C, 5-chloro-1- (1- [3- (2,3) -dihydro-6-methyl-2-oxo-1H-benzimidazol-1-yl) propyl (-4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one hemihydrate, mp 195.4 ° C and 5-chloro-1- (1- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -2-methylpropyl] -4-piperidinyl) -1,3-dihydro-2H -benzimidazol-2-one, mp 244 ° C.

Example 7 5-Chloro-1- (1- [3- (2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl) -propyl] -piperidinyl) -1,3-dihydro-2H-benzimidazole-2 -one.

A mixture of 38 parts of carbon disulfide, 6 parts of 1- [1- (3- [N- (2-aminophenyl) amino] propyl) -4-piperidinyl] -5-chloro-1,3-dihydro-2H-benzimidazole -2-one and 32 parts of ethanol, are stirred and refluxed 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-dimethylformamide and water to give 3 part of (45,5 ^) 5-chloro-1- (1- [3- (2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl) -propyl] -4-piperidinyl) -1 3-dihydro-2H-benzimidazol-2-one, mp 266.6 ° C.

Example 8 1- (1- [3- (6-chloro-1H-benzimidazol-1-yl) propyl] -4-piperidinyl) -1,3-dihydro-2H-benzomidazol-2-one.

A mixture of 4 parts of 1 - [(3- [N- (2-amino-5-chloro-phenyl) -amino] -propyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole-2 onion, 6 parts of concentrated hydrochloric acid solution and 30 parts of formic acid, are stirred and refluxed overnight. The reaction mixture is evaporated and water is added to the residue. It is then basified with 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 and crystallized from 2-propanol to give 1.1 parts (27%) of 1- (1- [1- (6-chloro-1H-benzimidazol-1-yl) -propyl] -4-piperidin-9-yl ) -1,3-dihydro-2H-benzimidazole-2-one; mp. 214.9 C.

Example 9 1- (3- [4- (5-Chloro-2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl) -1,3-dihydro-2H- benzimidazol-2-one.

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 disulphide and 120 parts of ethanol are stirred and refluxed for 24 hours, the reaction mixture is filtered after cooling and the filtrate is evaporated, the residue is crystallized from 2-propanol and the product is filtered off and recrystallized from ethanol to give 7.5 parts of (34) 1- ( 3 - / "4- (5-chloro-2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl) -1-piperidin-pyridinyl / propyl) ~ 1,3-dihydro-2H-benzimidazole-2 -one; sp.254,3 ° C.

As described above, 1- (3- [N- (2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl) -1-piperidinyl] propyl) -1,3-dihydro-2h-benzimidazole-2 -one; mp 248.5 ° C by reacting 1- [3- (4 - [(2-aminophenyl) amino] -1-piperidinyl) propyl] -1,3-dihydro-2H-benzimidazol-2-one with carbon disulfide.

6 2 6 6 7 35

Example 10 3-Acetyl-5-chloro-1 - (- [3 - (- acetyl-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -propyl] -4-piperidinyl) -1 , 3-dihydro-2H-benzimidazol-imidazol-2-one.

A mixture of 5 parts of 5-chloro-1- (1- / 3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -4-piperidinyl) -1,3-dihydro- ro-2H-benzimidazol-2-one, 10 parts of acetic anhydride and 90 parts of methylbenzene are stirred and refluxed overnight. The reaction mixture is cooled, water is added and basified with 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 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)]. yl) -propyl-4- (piperidinyl) -1-1,3-dihydro-2H-benzimidazol-2-one; mp. 185.3 ° C.

Example 11 (±) -5-Chloro-1- (1- [3- (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) -propyl] -4-piperidinyl) -1,3- dihydro-2H-benzimidazol-2-one 2,3-dihydroxybutanedicarboxylate ethanolate.

Mixed with a solution of 1 part 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 in 32 parts of ethanol, a solution of 0.35 parts of (+) - 2,3-dihydroxy-1,4-butanedioic acid in 8 parts of ethanol is added. After mixing, the products are allowed to crystallize. It is filtered and dried to give 1 part 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 2,3-dihydroxybutanedicarboxylic ethanolate; mp. 153.5 ° C.

Example 12 5-Chloro-1- (1- [3- (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) propyl] -4-piperidinyl) -1,3-dihydro-2H-benzimidazole -2-one hydrochloride hydrate.

Stirred solution of 1 part 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 in 20 parts of ethanol, gilded with gaseous hydrogen chloride. The hydrochloride salt formed 6 2 6 6 7 36 is crystallized while stirring. It is filtered 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, mp 195.7 ° C.

Example 13 5-Chloro-1- (1- [3- (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) propyl] -4-piperidinyl) -1,3-dihydro-2H- benzimidazole-2-one-hydro-chloride ethanolate.

Solution of 1 part of 5-chloro-1- (1- / 3- (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) -propyl] -4-piperidinyl) -1,3-dihydro -2H-Benzimidazol-1-one in 40 parts of ethanol is acidified with 2-propanol, which has previously been saturated with gaseous hydrogen chloride. While cooling, the formed hydrochloride salt is allowed to crystallize to give 1 part (83%) of 5-chloro-1- (1- / 5- / 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 14 5-Chloro-1- (1- [5- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -4-piperidinyl) -1,3-dihydro-2H- benzamidazol-2-one hemi- [R- (R *, R *) 7 (+) - 2,3-dihydroxybutanedioic carboxylate hydrate.

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 into the (+) - 2,3-dihydroxybutanedioate salt in 100 parts of water at reflux temperature. The solution is treated for 10 minutes with a mixture of 0.5 parts of activated carbon and 0.2 parts of hyflo. The latter is filtered over hyflon and the filtrate is cooled to form an oily precipitate, the oily product solidifies on heating for a short time. It is allowed to cool to room temperature and stirred for 3 hours at this temperature. The product is filtered, 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- (R *, R *) - 7 (+) - 2,3-dihydroxy-butanedicarboxylate hydrate: m.p. 184.1 ° C; C 11 H 18 + 5.13 ° (c = 1% ch 3 O 3).

Claims (2)

37 62 6 67 A process for the preparation of anti-emetic 1- (benzazolylalkyl) piperidine derivatives of the formula I and their pharmaceutically acceptable acid addition salts,? 3 -? 1 AU (CHO) -CH- (CHO) -N h -N 'NM (I) 2 m 2 n Wherein R and R are hydrogen, halogen, lower alkyl or trifluoromethyl, B is a divalent -N (L) -CO- or -N = CH radical attached to the benzene ring via a heteroatom, wherein L is hydrogen, lower alkyl, lower alkyl-3-carbonyl or lower alkenyl, R is hydrogen or methyl, m and n 78 represent an integer of 1 or 2, R and R represent hydrogen, halogen, lower alkyl or trifluoromethyl, Y is O or S, M is hydrogen, lower alkyl or lower alkylcarbonyl, and the dashed line is a possible bond between carbon atoms 3 and 4 of the piperidine ring, provided that when Y is S there is a single bond between carbon atoms 3 and 4 of the piperidine ring and M is hydrogen, characterized in that a) weather a compound of formula R3 B N- (CH-) -i: H- (CHO) -x (II) y / 2 m 2 n r1A-Nr2 12 3 wherein R, R, R, B, m and n X 3 is a reactive ester group derived from the corresponding alcohol to react with a compound of formula 38 6 2 6 6 7 a ~ \ _ A 7 8 wherein R, R, Y and M are as defined above, in a suitable in an organic solvent, or b) removing the protecting group P in a manner known per se from a compound of formula 0 Y Il 2 11 CR .. C / \ I / \ / \ y ~ {n LAC - A 2 IX X 8 R - RR ^ \ === s / ^ R ° 1 2 3 7 8 where, R , R, R, R, R, m, n, Y and M have the same meaning as above, or c) cyclizing a compound of formula Y E3, -vr I / \ H2 \ _F-, CH2) m-CH-, CH2 »nN \ .f ~ \ ΤΆ r \ C \ - riAC — Ar2 rV ^ C == ^ \ 8 1 2 3 7 8 where R, R, R, R, R, m, n, Y and M have the same meaning as above, with a suitable cyclizing agent in a manner known per se, or d) cyclizing a compound of formula 39 62667 fr ~ \? <CH2 »m-iH '<CH2> n ~ V_y \ H ^ NH2 r7X = Xr8 1 2 3 7 8 where R, R, R, R, R, B, m and n have the same meaning as above in a manner known per se using the appropriate a cyclizing agent, or e) N-alkylating or N-acylating in a manner known per se an N-unsubstituted compound of the formula I in which Y is O with an alkylating or acylating agent; and optionally converting the resulting compound of formula I to a pharmaceutically acceptable acid addition salt. Process according to claim 1 5-chloro-1- (1- [3- (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) -propyl] -4-piperidinyl) -1,3 -dihydro-2H-benzimidazol-2-one and its pharmaceutically acceptable acid addition salts, characterized in that 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one is reacted with 5-chloro-1, With 3-dihydro-1- (4-piperidinyl) -2H-benzimidazol-2-one and, if desired, the resulting compound is converted into a pharmaceutically acceptable acid addition salt. 62 6 6 7 40