WO1997035860A1

WO1997035860A1 - Novel benzimidazol derivatives having an affinity for the serotoninergic 5-ht3/5 ht4 receptors

Info

Publication number: WO1997035860A1
Application number: PCT/ES1997/000068
Authority: WO
Inventors: Maria Luz Lopez Rodriguez; Maria Jose Morcillo Ortega; Bellinda Benhamu Salama
Original assignee: Universidad Complutense De Madrid Rectorado
Priority date: 1996-03-22
Filing date: 1997-03-18
Publication date: 1997-10-02
Also published as: ES2109190A1; AU2160797A; ES2109190B1

Abstract

The present invention relates to new compounds having general formula (I), wherein X is oxygen or nitrogen; R is hydrogen or chlorine; R' is hydrogen, nitro or amino; and Y is azabicycle [x.y.z] alkyl, N-alkylpiperidyl or dialkylaminoalkyl. The invention discloses the processes for preparation of said compounds which have shown a high affinity for the serotoninergic 5-HT3 and/or 5-HT4 receptors. Therefore, they are useful from a therapeutical point of view in the treatment of emesa caused by chemotherapy, and in the treatment of gastrointestinal and neuronal troubles such as anxiety, psychosis, drug-addiction and cognitive troubles.

Description

NEW BENCIMIDAZOL DERIVATIVES AFFINED BY SEROTONINERGIC RECEIVERS 5-HT ₃ /5-HT ₄

The present invention concerns new compounds of general formula I. where X is oxygen or nitrogen, R is hydrogen or chlorine, R 'is hydrogen, nitro or amino, and Y is azabιcιclo [x and zjalkyl, N-alkylpyridyl or dialkylaminoalkyl

The methods of preparing said compounds are described, which have shown a high affinity for serotonergic receptors 5-HT ₃ and / or 5-HT ₄ , indicating their therapeutic interest in the treatment of emesis caused by chemotherapy, and in the treatment of gastrointestinal and neuronal disorders, such as anxiety, psychosis, drug dependence and cognitive disorders

BACKGROUND

Within the superfamily of serotonin receptors (5-HT, ₇ , F Saudou, WccuMed Chem Res, 1994, 4, 16), a major focus of current attention is the study of ligands with affinity for receptors. -HT _j and 5-HT ₄ , since they have a broad spectrum of pharmacological effects, and are involved in numerous physiological and physiopathological processes of the central and peripheral nervous systems (GJ Kilpatπck. KT Bunce. MB lyexs.Med Res Rev 1990, 10. 441. FD King, BJ Jones. GJ Sanger (Eds.) 5-Hydroxytryptamιne-3 Antagomsts CRC Press Receiver. Boca Raton, FL 1994, APDW Ford. DE Clarke, Λ / e? Res Rev, 1993. 13 (6 ), 633)

Some 5-HT ₃ receptor antagonists - ondansetron, grarusetron, tropisetron, zacopride, renzapride - show enormous therapeutic interest in the treatment of emesis caused by chemotherapy (MS Aapro. Drugs. 1991. 42 (4). 551) and in the treatment of gastrointestinal disorders (S Bingham and cois. J Pharm Pharmaco!. 1994. 4 ^~ . 219) or neuronal, such as anxiety (R Young. DN Johnson. Eur J Pharmacol. 1991

201. 151), psychosis (B Costal! \ Cois. Br J Pharmacol. 1987. 88 89P), drug dependence (B Costall \ cois. Br J Pharmacol. 1988. 95. 905P) and cognitive disorders (Y Chugh> cois. Eur J Pharmacol. 1991. 203. 121) However, in recent years it has been observed that the majority of 5-HT ₃ receptor antagonists are in turn 5-HT ₄ agonists. being of great difficulty obtaining selective ligands of these receptor subtypes, as well as the differentiation of their pharmacological actions This makes the synthesis of new Selective agents for the 5-HT ₃ or 5-HT ₄ receptor, an important objective for the study and characterization of both receptors, as well as an interesting alternative to the drugs marketed for the treatment of gastrointestinal and neuronal disorders.

DESCRIPTION

The present invention relates to new benzimidazole derivatives, which have shown a high affinity for 5-HT ₃ and / or 5-HT ₄ serotonergic receptors.

The new compounds are represented by the general formula I:

where X is oxygen or nitrogen; R is hydrogen or chlorine; R 'is hydrogen, nitro or amino; e And includes the following structures:

⁸ ^ ^

The compounds of general formula I have been synthesized by treatment of the benzimidazolcarboxylic acids II with 1,1'-carbonyldiimidazole (CDI) and subsequent reaction of the intermediate imidazolide with the corresponding aminoalcohol 1TJ or the corresponding diamine IV, in the presence of l, 8 -diazabicyclo [5 4 0] undec-7-ene (DBU) and anhydrous N, N-dimethylformamide (DMF) as the reaction solvent (Scheme I)

Ha: R = R '= H Hb: R = Cl, R' = H

Scheme I

Compounds I in which R 'is an amino group have been prepared by reduction of the corresponding nitro derivatives (R -niter)

4-Benzimidazolecarboxylic acid (lia) has been obtained following the procedure described by A Williams and G Salvadori (J Chem Soc, Perkin Trans 11 1972. 7, 883)

The synthesis of 6-chloro-4-benzimidazolecarboxylic acid (11b) has been carried out by condensation of 5-chloro-2,3-diaminotoluene (T Nyhammar and S Gπves, Acta Chem Scand

1986, B40, 583) with formic acid and subsequent oxidation of 6-chloro-4-methylbenzimidazole with potassium permanganate (Scheme II)

Scheme II 5-Chloro-4-rutro-7-benzimidazolcarboxylic acid has been prepared by nitration of 6-chloro-4-methylbenzimidazole and subsequent oxidation of 5-chloro-7-methyl-4-nitrobenzimidazole with potassium permanganate (Scheme III )

Scheme III

The following non-commercial HI amino alcohols and IV diamines have been obtained following procedures described in the literature exo-8-methyl-8-azabicyclo [3 2 l] octan-3- ol (AH Beckett et al., Tetrahedron 1959, 6, 319) , exσ-9-methyl-9-azabicyclo [3 3 l] nonan-3-ol (K Alder, HA Dortmann, Chem. Ber. 1953, 12, 1544), ew¿o-9-methyl-9-azabicyclo [ 3 3 l] nonan-3-ol (CL Zirkle and cois, J Org Chem 1961, 26, 395), l-methyl-4- piperidinol (E Alderova, V Seidlova, M Protiva, Chem Abs 1963, 8702c), 3 - piperidinopropanol (G Pandey, G Kumaraswamy, PY Reddy, Tetrahedron, 1992, 48 (38), 8295), exo-8-methyl-8-azabicyclo [3.2 1] octyl-3-amino (JR Bagley, TN Rιley, J Heterocycl Chem 1982, 19, 485), ewdo-9-methyl-9-azabιcycle [3 3 l] nonyl-3-amino (P Donatsch and cois, GB 2 125 398 A, Sandoz Ltd, 1984), 4-amino -l-methylpiperidine (P Brookes, RJ Terτ>. J Walker, J Chem Soc 1957, 3165) and 3-pιperidinopropylamine (T Ueda, K Ishizaki, Chem Pharm Bull, 1967, 5 (2), 228)

Exo-9-methyl-9-azabιcιclo [3 3 l] nonyl-3-amino has been synthesized by reducing the oxime of pseudopelletierine with Na in EtOH, as described in Scheme IV

Scheme IV The 4-amino-l-ethyl-, -1-propyl- and -1-butylpiperidines have been prepared by reducing the oximes of the corresponding 4-piperidones with LiAlH ₄ (Scheme V)

Scheme V

The (l-butyl-4-piperidylmethyl) amine has been synthesized according to the method described in Scheme VI

LιAlH ₄

-NBu "

H ₂ N

Scheme VI

L-Butyl-4-piperidylmethanol has been prepared following Scheme VII

Scheme VII EMBODIMENT OF THE INVENTION

EXAMPLE 1

6-Chloro-4-benzimidazolecarboxylic acid, Ilb

(a) 6-Chloro-4-methylbenzimidazole

A solution of 3.3 g (21 mmol) of 5-chloro-2,3-diaminotoluene in 2.9 g (60 mmol) of 98% formic acid and 40 mL of water is refluxed (in a water bath) during 6 hours (c cf) The reaction mixture is cooled in an ice bath and treated with a cold aqueous solution of potassium hydroxide Í to basic pH, precipitating 3.4 g (98%) of the 6-chloro-

4-methylbenzimidazole P f 172.5-173.5 ° C (chloroform)

(b) 6-Chloro-4-benzimidazolecarboxylic acid

To a solution of 2.2 g (13 mmol) of 6-chloro-4-methylbenzimidazole in 130 mL of Ín sodium hydroxide heated in a water bath, 5 portions of 2.1 g of potassium permanganate are added at intervals of 1 hour After the last addition, the reaction mixture is refluxed for a further 2 hours (ccf) Then the manganese dioxide is filtered hot, the solvent is removed under reduced pressure and the residue is purified by gel column chromatography. silica (chloroform / methanol 9 l → l 1), 1.2 g (40%) of Eíb being isolated in the form of hydrochloride P f> 300 ° C (diluted hydrochloric acid)

EXAMPLE 2

5-Chloro-4-nitro-7-benzimidazolecarboxylic acid,

(a) 5-Chloro-7-methyl-4-nitrobenzimidazole

To a solution of 2.0 g (12 mmol) of 6-chloro-4-methylbenzimidazole in 6 mL of sulfuric acid concentrated at 0 ° C, a mixture of 0.6 mL of nitric acid is added dropwise 70% and 0.6 mL of concentrated sulfuric acid, and the reaction is maintained below 5 ° C for 2 hours. Then, 7 mL of ice water is added and treated with ammonium hydroxide to basic pH. The resulting precipitate is purified. by silica gel column chromatography (ethyl acetate / hexane 2 8 → 6 4), obtaining 1.5 g (59%) of the desired isomer 5-chloro-7-methyl-4-nιtrobenzimdazol P f 264-265 ° C (chloroform)

(b) 5-Chloro-4-nitro-7-benzimidazolecarboxylic acid

To a solution of 1.0 g (5 mmol) of 5-chloro-7-methyl-4-nitrobenzimidazole in 50 mL of 1 N sodium hydroxide heated in a water bath, 4 portions of 0.7 g (5 g) are added. mmol) of potassium permanganate, at 1 hour intervals After the last addition, the reaction mixture is refluxed for a further 2 hours (cef) Then, the manganese dioxide is filtered hot, the solvent is removed under reduced pressure and the residue is purified by silica gel column chromatography (chloroform / methanol 9 l → 1 1), 0.5 g (38%) of hydrochloride is isolated pf> 300 ° C (diluted hydrochloric acid)

EXAMPLE 3

4-benzimidazole carboxylate of "í / o-9-methyl-9-azabicyclo [3 3.1] non-3-yl, Id

To a suspension of 2.0 g (10 mmol) Gives in 10 mL of anhydrous N, N-dimethylformamide, under nitrogen atmosphere, 1.6 g (10 mmol) of l, r-carbonyldiimidazole and the resulting solution are added it is heated at 40 ° C for 1 hour. Next, a solution of 3.1 g (20mmol) of e 'í / o-9-methyl-9-azabicyclo [3 3 l] nonan-3- is added dropwise ol and 1.5 g (10 mmol) of l, 8-diazabicyclo [5 4 0] undec-7-ene in 20 mL of anhydrous N, N-dimethylformamide The reaction mixture is heated at 50 ° C for 20 hours in nitrogen atmosphere The solvent is evaporated under reduced pressure and the resulting oil is dissolved in 100 mL of chloroform, washed with 40 mL of water and then with 40 mL of 20% aqueous potassium carbonate. The organic extracts are dried over MgSO ₄ and The solvent is removed under reduced pressure, isolating an oil that is purified by silica gel column chromatography (dichloromethane / methanol 1 1) The solid obtained (1.2 g) is crystallized from chloroform / é ethyl tether P f 198.5-200.5 ° C

Similarly the following compounds were prepared

? X 4-benzimidazolcarboxylate ^, o-8-methyl-8-azabicyclo [3 2 l] oct-3-yl P f 164-166 ° C (chloroform / ethyl ether), έτκ / o- 4-benzimidazole carboxylate 8-methyl-8-azabicιclo [3 2.1] oct-3-ilo P f 205-207 ° C

(chloroform / ethyl ether). Ib Exo9-Methyl-9-azabicyclo [3 3 l] non-3-yl P-76-78 ° C 4-benzimidazolecarboxylate

(acetone / ethyl ether), le

L-azabicyclo [2 2 2] oct-3-yl P-210-212 ° C (chloroform) 4-benzimidazolecarboxylate

/ ethyl ether), l-methyl-4-piperidyl P-163-165 ° C (water / ethyl ether) le-4-benzimidazolcarboxylate, lf

L-Butyl-4-piperidylmethyl 4-benzimidazolecarboxylate P f 159-161 ° C (acetone), lg

2- (N, N-dmethylamino) ethyl 4-benzimidazolecarboxylate P f 132.5-134.5 ° C (chloroform

/ ethyl ether), lh

2- (N, N-diethylamino) ethyl 4-benzymidazolecarboxylate P f 139-141 ° C (chloroform / ethyl ether), li

2-Piperidinoethyl 4-bencirnidazolecarboxylate P f 148-150 ° C (ethyl acetate), lj

3-Piperidinopropyl 4-benzimidazole carboxylate P f 153-155 ° C (acetone / ethyl ether), lk

Ewcfo-8-methyl-8-azabicyclo [3 2 l] oct-3-yl P f 248- 6-Chloro-4-benzimidazolcarboxylate

250 ° C (d) (chloroform / ethyl ether), II 6-Chloro-4-benzimidazolcarboxylate of exo-9-methyl-9-azabonyclo [3 3 l] non-3-üo P f 195-

197 ° C (chloroform / ethyl ether), lm

E / κ / o-9-methyl-9-azabicyclo [3 3 1] non-3-yl P f 240- 6-Chloro-4-benzimidazolcarboxylate

242 ° C (acetone / ethyl ether), ln

1-Azabicyclo [2 2 2] oct-3-yl P-201-203 ° C (ethyl ether / hexane) 6-Chloro-4-benzimidazolcarboxylate, lo

EXAMPLE 4

N- (l-Azabicyclo [2 2 2] oct-3-yl) -6-chloro-4-benzimidazolecarboxamide, 2q

To a solution of 2.3 g (10 mmol) of Ilb in 10 mL of anhydrous N, N-dimethylformamide under a nitrogen atmosphere, 1.6 g (10 mmol) of 1,1'-carbonyldiimidazole are added and the solution The resulting mixture is heated at 40 ° C for 1 hour. Next, a solution of 2.2 g (20 mmol) of 3-aminoquinuclidine (previously released from its hydrochloride form) and 1.5 g (10 mmol) are added dropwise. ) of l, 8-dιazabicyclo [5 4 0] undec-7-ene in 20 mL of anhydrous N, N-dιmethylformamide The reaction mixture is heated at 50 ° C for 24 hours under nitrogen atmosphere The solvent evaporates under pressure reduced and the resulting oil is dissolved in 100 mL of chloroform, washed with 40 mL of water and then with 40 mL of 20% aqueous potassium carbonate. The organic extracts are dried over MgSO ₄ and the solvent is removed under reduced pressure, isolated an oil that it is purified by silica gel column chromatography (chloroform / methane! 9 1) The solid obtained (1.0 g) is crystallized from water P f 264-266 ° C

Similarly the following compounds were prepared

N- (exo-8-Methyl-8-azabicyclo [3 2 l] oct-3-yl) -4-benzimidazolcarboxamide P f 233, 5-235, 5 ° C

(chloroform / ethyl ether), 2nd

N- (exc> -9-Methyl-9-azabcycle [3 3 l] non-3-yl) -4-benzimidazolcarboxamide P f 203-205 ° C

(acetone), 2b N- (encfo-9-Methyl-9-azabicyclo [3 3 l] non-3-yl) -4-benzimidazolecarboxamide P f 240-242 ° C

(methanol / ethyl acetate), 2c

N- (l-Azabicιclo [2 2 2] oct-3-yl) -4-benzimidazolecarboxamide P f 196-198 ° C (methanol / ethyl acetate), 2d

N- (l-Methyl-4-piperidyl) -4-benzimidazolcarboxamide P f 122-124 ° C (water), 2e N- (1-Ethyl-4-pperperyl) -4-benzimidazolecarboxamide P f 126-128 ° C ( water), 2f

N- (l-Propyl-4-piperidU) -4-benzimidazolcarboxamide P f 1 19-121 ° C (acetone / ethyl ether),

2 g

N- (1-Butyl-4-piperidyl) -4-benzimidazolcarboxamide P f 94-97 ° C (acetone / water), 2h

N- (l-Butyl-4-piperidylmethyl) -4-benzimidazolcarboxamide P f 122-125 ° C (ethyl acetate), 2i

N- [2- (N, N-Dimethyamin) eti] -4-benzimidazolcarboxamide P f 79-81 ° C (chloroform / ethyl ether), 2j

N- [2- (N, N-Diethylamino) ethyl] -4-benzimidazolcarboxamide (oil), 2k

N- (2-Piperidinoethyl) -4-benzimidazolcarboxamide (oil), 21 N- (3-Piperidinopropyl) -4-benzimidazolecarboxamide P f 161-164 ° C (acetone), 2m

N- (αco-8-Methyl-8-azabicicIo [3.2 l] oct-3-yl) -6-chloro-4-benzimidazolecarboxamide P f 255-

257 ° C (water), 2n

N- (ero-9-Methyl-9-azabicyclo [3 3 l] non-3-yl) -6-chloro-4-benzimidazolecarboxamide P f 198-

200 ° C (acetone), 2nd N- (e / ifo-9-Methyl-9-azabicιclo [3 3 l] non-3-yl) -6-chloro-4-benzimidazolecarboxamide

P f> 300 ° C (chloroform), 2p

N- (l-Methyl-4-piperidyl) -6-chloro-4-benzimidazolcarboxamide P f 238-239T (acetone

/ ethyl acetate), 2nd

N- (l-Azabicyclo [2.22] oct-3-yl> 5-chloro-4-nitro-7-benzimidazolcarboxarnide P f 265-266 ° C (ethyl acetate), 2s EXAMPLE 5

CONSTANTS OF AFFINITY (K _t ) BY SEROTONINERGIC RECEIVER

5-HT ₃

The affinities of the compounds of general structure I for the serotonergic 5-HT ₃ receptor in rat cerebral cortex membranes, in vitro, were determined by radioligand displacement techniques, using [ ³ H] LY 278584 ([ ³ H] - 1- methyl-N- (enc / o-8-methyl-8-azabicyclo [3.2. L] oct-3-yl) -lH-3-indazolcarboxamide) as a selective ligand.

Process

Experimental animals (male albino rats, Ratíus norvegicus albinus), Sprague-Dawley breed, weighing approximately 200 g, are sacrificed by decapitation. Brains are quickly removed and frozen in liquid nitrogen. The tissue is stored at -80 ° C until it is used.

The procedure of Wong and cois has been followed. (Eur. J. Phαrmαcol. 1989, 166, 107) described below.

The cerebral cortex is homogenized in 9 volumes of 0.32 M sucrose and centrifuged at 1000 xg for 10 min, at 4 ° C. The sediment is neglected and the supernatant is centrifuged at 17000 xg for 20 min, at 4 ° C. The sediment is washed twice by resuspension in 60 volumes of 50 mM Tris-HCl buffer (pH 7.4 at 25 ^C C), and centrifugation at 48000 xg for 10 min, at 4 ° C. After the second wash the resuspended sediment is incubated at 37 ° C for 10 min. The membranes are centrifuged again under the same conditions and the sediment is resuspended in 2.75 volumes of the incubation buffer, consisting of 50 mM Tris-HCl, 10 μM pargiline, 0.6 mM ascorbic acid and 5 mM CaCl ₂ (pH 7 , 4 to 25 ° C). 100 μL fractions (approximately 2 mg / mL protein) of the final membrane suspension are incubated for 30 min at 25 ° C with

[ ³ H] LY 278584 (Amersham, 83 Ci / mmol) 0.7 nM, in the presence or absence of the compound under study at 1 µM concentration, in a final volume of 2 mL of incubation buffer. Nonspecific binding is determined with 10 μM 5-HT. The bound radioactive ligands are separated from the free ones by vacuum filtration on Whatman GF / B filters, washed twice with 4 mL of 50 mM Tris-HCl buffer. After drying the filters for 1 hour at At 60 ° C, 4 mL of scintillation liquid (Aquasol) is added and the membrane-bound radioactivity is measured by liquid scintillation spectrometry

In the case of active compounds (those whose inhibition is> 55%), their Cl ₅₀ has been determined by non-linear regression of the displacement curve obtained for 6 different concentrations of the compound (10 ^'5 -10 ¹⁰ M), using the Equation% EU ^~ 100 (1 - C *) / (CI ₅₀ ^b + C *). The conversion of CL, ₀ to K, has been carried out with the equation / ζ = IC „/ (1 + VK _D ) (Y Cheng, WH Prusoff, Biochem Pharmacol. 1973, 22, 3099), where L is the radioligand concentration and K _D its dissociation constant

The results obtained are shown in Table 1, together with the affinity constants of the tropisetron as a reference

EXAMPLE 5

CONSTANTS OF AFFINITY (A,) BY SEROTONINERGIC RECEIVER 5-HT ₄

The affinities of the compounds of general structure I for the serotonergic 5-HT ₄ receptor in rat brain striatum, m vitro, were determined by radioligand displacement techniques, using [ ³ H] GR 1 13808 ([ ³ H] L- [2 - [(Methylsulfonyl) amino] ethyl] -4-piperidylmethyl) -1-methyl-lH-3-indolcarboxylate) as selective ligand

Process

In order to obtain the rat brains, we proceed in the same way as described for the 5-HT ₃ receptor

The procedure of Grossman and cois has been followed (Br J Pharmacol. 1993. 109. 618) described below.

The striatum is rapidly dissected on ice, homogenized in 15 volumes of 50 mM HEPES buffer (pH 7.4 at 4 ° C) and centrifuged at 48000 xg for 10 min, at 4 ° C. The supernatant is neglected and the sediment resuspended in 4.5 mL

(approximately 1500 μg of protein) of the same buffer Fractions of 100 μL of the final suspension are incubated for 30 min at 37 ° C with [ ³ H] GR 1 13808 (Amersham, 85 Ci / mmol) 0.2 nM, in the presence or absence of the compound under study at 1 µM concentration, in a final volume of 1 mL of incubation buffer. Non-specific binding is determined with 5-HT 30 μM. The bound radioactive ligands are separated from the free ones by vacuum filtration on Whatman GF / B filters, washed once with 4 mL of 50 mM HEPES buffer. After drying the filters for 1 hour at 60 ° C, 4 mL of scintillation liquid (Aquasol) are added and the radioactivity bound to the membranes is measured by liquid scintillation spectrometry.

In the case of active compounds (those whose inhibition is> 55%), their IC ₅₀ has been determined in the same way as described for the 5-HT ₃ receptor.

The results obtained are shown in Table 1, together with the affinity constants of GR 113808 as a reference.

Table 1. Affinity data of compounds of eneral structure I or 5-HT 5-HT receptors

'The data represent the average value of K, (nM) and its standard error of two to four individual experiments performed in triplicate.

The terms in which this report has been described must always be taken in a broad and non-limiting manner.

Claims

1.- Compound of general formula I

I

in which:

X is oxygen or nitrogen; R is hydrogen or chlorine; R 'is hydrogen, nitro or amino; and Y is azabicyclo [x.y.z] alkyl, N-alkylpiperidyl or dialkylaminoalkyl.

2. A compound according to claim 1, wherein X is oxygen; R and R 'are hydrogens; and Y is exo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl, ewc / o-8-methyl-8-azabicyclo- [3.2.1] oct-3-yl, exo-9- methyl-9-azabicyclo [3.3.1] non-3-yl, and 'íiO-9-methyl-9-azabicyclo [3.3.1] - non-3-ilo, l-azabicyclo [2.2.2] oct-3 -yl, l-methyl-4-piperidyl, l-butyl-4-piperidylmethyl, 2- (N, N-dimethylamino) ethyl, 2- (N, N-diethylamino) ethyl, 2-piperidinoethyl or 3-piperidinopropyl.

3. A compound according to claim 1, wherein X is oxygen; R is chlorine; R 'is hydrogen; and Y is eAicfo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl, exo9-methyl-9-azabicyclo [3.3.1] - non-3-yl, e / κ / o-9- methyl-9-azabicyclo [3.3.1] non-3-yl or l-azabicyclo [2.2.2] oct-3-yl.

4. A compound according to claim 1, wherein X is nitrogen; R and R 'are hydrogens; and Y is exo-8-methyl-8-azabicyclo [3.2. l] oct-3-yl, exo-9-methyl-9-azabicyclo [3.3.1] - non-3-ilo, e / Jí / r> -9-methyl-9-azabicyclo [3.3.1] non- 3-yl, l-azabicyclo [2.2.2 Joct-3-yl, l-methyl-4- piperidyl, l-ethyl-4-piperidyl, l-propyl-4-piperidyl, l-butyl-4-piperidyl, 1 - butyl-4-piperidylmethyl, 2- (N, N-dimethylamino) ethyl, 2- (N, N-diethylamino) ethyl, 2-piperidinoethyl or 3- piperidinopropyl.

5. A compound according to claim 1, wherein X is nitrogen; R is chlorine; R 'is hydrogen; and Y is exo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl, exo-9-methyl-9-azabicyclo [3.3.1] - non-3-yl, <? rtdo-9-methyl-9-azabicyclo [3.3 l] non-3-yl, l-azabicyclo [2 2 2] oct-3-yl or 1-methyl-4-piperidinyl

6. A compound according to claim 1, wherein X is nitrogen, R is chlorine, R 'is nitro, and Y is 1-azabicyclo [2 2 2] oct-3-yl

7.- A process for obtaining esters and amides of formula I, characterized by the reaction of carboxylic acids II with amino alcohols UJ or diamines IV, respectively, in the presence of l, r-carbonyldümidazole (CDI) and 1, 8- diazabicyclo [5 4.0] undec-7-ene (DBU) in anhydrous N, N-dimethylformamide (DMF) as solvent

8.- A process for obtaining 6-chloro-4-benzimidazolecarboxylic acid (Hb) by condensation of 5-chloro-2,3-diaminotoluene with formic acid and subsequent oxidation with potassium permanganate.

9.- A process for obtaining 5-cIoro-4-nitro-7- benzimidazolcarboxylic acid (De) by nitration of 6-chloro-4-methylbenzimidazole and subsequent oxidation with potassium permanganate.

10.- Compounds of general formula I for use as drugs

11.- Use of the compounds of general formula I for the preparation of a drug for the treatment of antiemesis, gastrointestinal disorders or CNS disorders, such as anxiety, psychosis, drug dependence or cognitive disorders.