MXPA99007585A

MXPA99007585A - 4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-one derivatives, theirpreparation and their use as dopamine autoreceptor (d2) agonists

Info

Publication number: MXPA99007585A
Application number: MXPA/A/1999/007585A
Authority: MX
Inventors: Eric Mewshaw Richard; Albert Nelson James; Shantilal Shah Uresh
Original assignee: Wyeth
Priority date: 1997-02-18
Filing date: 1999-08-17
Publication date: 2000-06-01

Abstract

Disclosed are compounds of formula (I), wherein R1 is hydrogen or C1-C6 alkyl;R2 is selected from hydrogen, straight-chain and branched C1-C10 alkyl, cyclohexylmethyl or -(CH2)mAr where Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from C1-C6 alkyl, halogen, C1-C6 alkoxy and trifluoromethyl;or NR1R2 is 1,2,3,4-tetrahydroquinolin-1-yl or 1,2,3,4-tetrahydroisoquinolin-2-yl;m is 1-5;n is 1 or 2;R3 is hydrogen or C1-C6 alkyl;Y is halogen, C1-C6 alkyl, and C1-C6 alkoxy;or a pharmaceutically acceptable salt thereof, which are dopamine autoreceptor agonists and as such are useful in the treatment of schizophrenia, Parkinson's disease, Tourette's syndrome, alcohol addiction and drug addiction.

Description

DERIVATIVES OF -AMINOALCOXI-1, 3-DIHYDROBENZOIMIDAZOL-2-ONA, ITS PREPARATION AND ITS USE AS AGONISTS OF THE DOPAMINE AUTORRECEPTOR (D2) Field of the Invention The present invention relates to a series of 4-aminoalkoxy-l, 3-dihydrobenzoimidazol-2-ones having dopaminergic properties, and thus have utility in the treatment of Parkinson's disease, Tourette's syndrome, schizophrenia and addition to alcohol and drugs.

Background of the Invention The compounds of this invention are dopamine agonists having various fatty acids of intrinsic activity, and are essentially free of extrapyramidal side effects. Some of the compounds are selective autoreceptor agonists, and therefore, partial agonists (ie, activate only autoreceptors against post-synaptic dopamine D2 receptors). Efforts to induce anti-psychotic activity with dopamine autoreceptor agonists REF .: 30943 have been successful (Dorsini et al, Adv. Biochem, Psychopharmacol., 16, 645-648, 1977, Tamminga et al., Science, 200, 567-568, and Tamminga et al., Psychiatry, 398-402, 1986) . As selective autoreceptor agonists, the compounds of the invention provide functional modulation of brain dopamine systems without excessive blockade of post-synaptic dopamine receptors, which have been found to be responsible for the serious side effects frequently exhibited by agents that were otherwise clinically effective for the treatment of schizophrenia. Activation of dopamine autoreceptors results in reduced neuronal discharge, as well as inhibition of dopamine synthesis and release, and thus provides a means of controlling the hyperactivity of dopaminergic systems. It was also found that the compounds of this invention have a high intrinsic activity and therefore can behave like the natural neurotransmitter, ie, as full agonists. As such, they are useful in the treatment of diseases that have abnormal concentrations of dopamine and could be used as surrogates of dopamine, such as schizophrenia, Parkinson's disease and Tourette's syndrome. Such agents are partial agonists at the post-synaptic dopamine D2 receptor and are thereby useful in the treatment of addition to alcohol and drugs. In Belgian Patent No. 850,166, Ciba-Geigy discloses compounds represented by the compound of the formula below, which both have and β-adrenergic properties and are useful as cardiovascular and antihypertensive agents.

CGP-12177 Brief Description of the Invention The compounds of this invention are 4-aminoalkoxy-1,3-dihydro-benzoimidazol-2-ones which are illustrated by Formula I below: wherein R1 is hydrogen or alkyl of 1 to 6 carbon atoms; R 2 is selected from hydrogen, alkyl of 1 to 10 straight carbon atoms or branched chain, cyclohexyl ethyl or - (CH) mAr wherein Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each Optionally substituted by one or two substituents independently selected from alkyl of 1 to 6 carbon atoms, halogen, alkoxide of 1 to 6 carbon atoms and trifluoromethyl; 15 or NR1R2 is 1, 2, 3, 4-1-tetrahydroquinol-l-yl or 1,2,3,4-tetrahydroisoquinolin-2-yl; m is 1 - 5; n is 1 or 2; R3 is hydrogen or alkyl of 1 to 6 carbon atoms carbon; Y is halogen, alkyl of 1 to 6 carbon atoms, and alkoxy of 1 to 6 carbon atoms; and the pharmaceutically acceptable salts thereof. The acid addition salts can be formed with a compound of the invention and a pharmaceutically acceptable acid including, but not limited to, the hydrochloride, hydrobromide, hydroiodide salts, sulfate, phosphate, nitrate, acetate, fumarate, succinate, citrate, maleate, lactate, and benzoate. The compounds of this invention are dopamine autoreceptor agonists, that is, they serve to modulate the synthesis and release of the neurotransmitter dopamine. They are thus useful for the treatment of disorders of the dopaminergic system, such as schizophrenia, Parkinson's disease and Tourette's syndrome. Such agents are partial agonists at the post-synaptic dopamine D2 receptor, and are thereby useful in the treatment of alcohol and drug additions.

Detailed description of the invention The compounds of Formula I are generally prepared by the general sequence depicted in Schemes I-IV. When one or both of R1 and R2 is hydrogen, it is desirable to protect the basic nitrogen with a suitable protecting group such as the trifluoroacetyl group or the t-butyloxycarbonyl group. Scheme I represents a process for preparing a compound of the invention, wherein R3 is H.

-Scheme I Nickel Ranßy HCl salt Scheme II shows a synthetic route for the compounds of the invention, where R ~ is not H. Scheme II Boc BOC Scheme III shows a synthetic route for compounds of the invention wherein none of R1 and R2 is H. Scheme III Scheme IV shows the procedure used to prepare an intermediary where Y is Cl. Scheme IV n The following specific examples illustrate synthetic procedures for the preparation of intermediates and compounds of the invention, and should not be construed as limiting the scope of this disclosure. Those skilled in the art of organic synthesis may be aware of still other routes for preparing the compounds of the invention. The reagents and intermediates are either commercially available or can be prepared according to standard procedures of the literature.

Intermediate 2- (2-Chloro-ethoxy) -6-nitro-enylamine Method 1. To a solution of 2-amino-3-nitrophenol (5.0 g, 32.4 mmol), triphenylphosphine (12.8 g, 48.7 mmol) and 2-chloroethanol (3.9 g, 48.7 mmol) in tetrahydrofuran (120 ml) at 0-5 ° C was added a solution of diethyl azodicarboxylate for 30 minutes. (8.5 g, 48.7 mmoles) in tetrahydrofuran (75 mi). The mixture was heated to 23 ° C and stirred for 18 hours. The solvent was removed under vacuum to give a dark brown oil. Purification by chromatography (1.3 kg of silica gel, 30% hexane-ethyl acetate) yielded 3.1 g (44.2%) of an orange solid, m.p. 71-73 ° C; MS (+) PBEI m / e 216/218 (M +). Elemental analysis for C8H9CIN2O3: Calculated: C, 44.36; H, 4.19; N, 12.93 Found: C, 44.45; H, 4.02; N, 12.97 Method 2. A paste containing 2-amino-3-nitrophenol (32.0 g, 0.208 moles), 1,2-dichloroethane (260.0 g, 2. 65 moles), potassium carbonate (35.0 g, 0.252 mol) and 2-butanone (750 ml) was heated to reflux for 24 hours. The mixture was cooled, filtered and the solids were washed with ethyl acetate. The filtrate was concentrated to an oily residue which was dissolved in ethyl acetate (500 ml). The organic layer was washed with 1 N sodium hydroxide (250 ml), water (500 ml), and saline (2X 500 ml), dried over anhydrous magnesium sulfate. Concentration of the filtered solution and trituration of the residue with hexane gave 37.8 g (84.6%) of the product as an orange solid, m.p. 71.73 ° C; MS (+) PBEI m / e 216/218 (M +).

Intermediate Ib 2- (3-Bro or -propoxy) -6-nitro-phenylamine Following the procedure of method 2 above, and using 1,3-dibromopropane, the title compound was obtained as a yellow solid, (78.7%) pf 88-89 ° C; MS The m / e 274 / '276 (M +). Elemental analysis for C? H11BrN203: Calculated: C, 39.29; H, 4.03; N, 10.18 Found: C, 39.71; H, 3.91; N, 10.27 Intermediate 2a 2- (2-Benzylamino-ethoxy) -6-nitro-phenylamine A mixture of 2- (2-chloro-ethoxy) -6-nitro-phenylamine (l_a, 3.0 g, 13.8 mmol) and benzylamine (9.0 g, 84.0 mmol) was heated without mixing at 100-110 ° C for 6 hours. The excess benzylamine was removed by distillation under vacuum (70-75 ° C / 1.36 x 10-4 kg / cm 2 (0.1 mm of mercury) .The residue was poured into 1 N sodium hydroxide (300 ml) and extracted with Ethyl acetate (2 X, 300 mL) The combined organic layer was washed with water (2X, 300 mL), and saline (300 mL) The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed under vacuum to give 5.1 g of the crude red oil. (500 g of silica gel, ethyl acetate: 2 M NH 3 in methanol, 20: 1) ratio 3.54 g (89.3%) of a red semisolid of m.p. 33-60 ° C; MS The m / e 287 (M +). Elemental analysis for C15H17N3O3 Calculated: C, 62.71; H, 5.96; N, 14.62 Found: C, 62.64; H, 6.04; N, 14.23 xDMSO can be used as a solvent in this reaction. Using this general procedure and using 2- (2-chloro-ethoxy) -6-nitro-phenylamine or 2- (3-bromo-propoxy) -6-nitro-phenylamine or 4-chloro-2- (2-chloro-ethoxy) ) -6-nitro-phenylamine and 4-methyl-benzylamine, 1-naphthalene-methylamine, 4-tert-butyl-benzylamine, thiophen-2-methyl-amine, 4-chloro-benzylamine, thiophene-3-methylamine, 1, 2, 3, 4-tetrahydroisoquinoline or 3-phenyl-1- propylamine the following intermediates 2b-21 were produced, respectively: 2b 2- [2- (4-Methyl-benzylamino) -ethoxy] -6-nitro-f-enylamine as a yellow solid (89%), m.p. 55-57 ° C; The m / e 301 (M +). Elemental analysis for C? 6H? 9N3? 3: Calculated: C, 62.71; H, 5.96; N, 14.62 Found: C, 62.64; H, 6.04; N, 14.23 2c 2- (3-benzylamino-propoxy) -6-nitro-phenylamine as a viscous orange oil (85.5%); EM The m / e 301 (M +). Elemental analysis for C 16 H 19 N 3 O 3: Calculated: C, 63.77; H, 6.36; N, 13.94 Found: C, 63.66; H, 6.28; N, 13.89 2d 2-. { 2- [(Naphthalen-1-ylmethyl) -amino] -ethoxy} - 6-N-tro-phenylamine as a yellow solid (76.3%), p.f. 66-67 ° C; MS The m / e 337 (M +). Elemental analysis for C19H3.9N3O3: Calculated: C, 67.64; H, 5.68; N, 12.45 Found: C, 67.20; H, 5.66; N, 12.26 2e 2- [2- (4-tert-Butylbenzylamino) -ethoxy] -6-nitrophenylamine as a viscous orange oil (83.3%); MS The m / e 343 (M +). Elemental analysis for Ci9H25N3? 3 »0.25 H20: Calculated: C, 65.59; H, 7.39; N, 12.07 Found: C, 65.89; H, 7.20; N, 11.94 2f 2-Nitro-6-. { 2- [(thiophen-2-ylmethyl) -amino] -ethoxy} phenylamine as a red semisolid material (88.5%); MS The m / e 389 (M +). Elemental analysis for C13H15N3O3S: Calculated: C, 53.23; H, 5.15; N, 14.32 Found: C, 52.86; H, 4.93; N, 14.15 2g 2- [2- (4-Chloro-benzylamino) -ethoxy] -6-nitro-phenylamine as an orange solid (87.8%), m.p. 61-62 ° C; EM The m / e 322/324 (M +). Elemental analysis for C? 5H? 6N3O3 «0.25 H20: Calculated: C, 55.22; H, 5.10; N, 12.88 Found: C, 55.27; H, 4.96; N, 12.88 2h 2- (2-Benzylamino-ethoxy) -4-chloro-6-ni tro-phenylamine as an orange-brown colored solid (54.0%), m.p. 87-88 ° C; EM The m / e 321/323 (M +). Elemental analysis for C? 5H? 6ClN303: Calculated: C, 55.99; H, 5.01; N, 13.06 Found: C, 55.85; H, 4.90; N, 13.13 2i 4-Chloro-2-ni tro-6-. { 2- [(thiophen-2-ylmethyl) -amino] -ethoxy} phenylamine as a yellow solid (44.0%), m.p. 74-75 ° C; EM The m / e 327/329 (M +). Elemental analysis for C? 3H? ClN302S: Calculated: C, 47.67; H, 4.33; N, 12.75 Found: C, 47.54; H, 4.11; N, 13.06 2 j 4-chloro-2-nitro-6-. { 2- [(thiophen-3-ylmethyl) amino] -ethoxy} phenylamine as a yellow solid (33.3%), m.p. 77-78 ° C; EM The m / e 327/329 (M +). Elemental analysis for C? 3H 4C1N302S: Calculated: C, 47.67; H, 4.33; N, 12.75 Found: C, 47.54; H, 4.18; N, 12.80 2k 2- [2- (3,4-Dihydro-lH-isoquinolin-2-yl) -ethoxy] -6-nitro-phenylamine as a yellow solid (87.1%), m.p. 95-97 ° C; MS The m / e 313 (M +). Elementary analysis for : Calculated: C, 65.16; H, 6.11; N, 13.41 Found: C, 64.87; H, 6.11; N, 13.40 21 2-Nitro-6- [2- (-phenyl-propylamino) -ethoxy] -phenylamine as a viscous orange oil (83.9%), MS m / e 315 (M +). Elemental analysis for CpH2? N3? 3 * 0.25 H20: Calculated: C, 63.83; H, 6.77; N, 13.14 'Found: C, 63.90; H, 6.56; N, 13.07 Intermediary 3a N- [2-. { 2 -Ami no -3-nor tro-f enoxi) -ethyl] -N-benzyl-2, 2,2-trifluoroacetamide To a solution of 2- (2-benzylamino-ethoxy) -6-nitro-phenylamine (2a, 0.5 g, 1.74 mmol) and triethylamine (0.32 mL, 3.48 mmol) in anhydrous methylene chloride (10 mL) at 23 ° C. trifluoroacetic anhydride (0.32 ml, 2.26 mmol) was added. After 2 hours the reaction was diluted with ether and washed with saturated sodium bicarbonate (3 x 80 mL) and the organic layer was dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave 0.55 g (81.7%) of a yellow solid, m.p. 134-135 ° C; MS The m / e 383 (M +). Elemental analysis for Ci7Hi6FN304: Calculated: C, 53.27; H, 4.21; N, 10.96 Found: C, 53.09; H, 4.35; N, 10.93. Following this general procedure, and using 2- [2- (4-methyl-benzylamino) -ethoxy] -6-nitro-phenylamine, 2- (3-benzylamino-propoxy) -6-nitro-phenylamine, 2-. { 2- [(naphthalen-1-ylmethyl) -amino] -ethoxy} -6-nitro-phenylamine, 2- [2- (4-tert-butylbenzylamino) -ethoxy] -6-nitro-phenyl-amine, 2-nitro-6-. { 2- [(thiophen-2-ylmethyl) -amino] -ethoxy} phenylamine, 2- [2- (4-chloro-benzylamino) -ethoxy] -6-nitro-phenylamine, 2- (2-benzylamino-ethoxy) -4-chloro-6-nitro-phenylamine, 4-chloro-2 -nitro-6-. { 2- [(thiophen-2-ylmethyl) -amino] -ethoxy-phenylamine, 4-chloro-2-nitro-6-. { 2- [(thiophen-3-ylmethyl) - amino] - ethoxy} - f eni lamina and 2-n-tro- 6- [2 - (3-f eni -propolamino) -ethoxy] -phenylamine gave respectively: 3b N- [2- (2-amino-3-nitro-phenoxy) -ethyl] -2,2,2-tri-luoro-N- (4-methyl-benzyl) -acetamide as a yellow solid (79%), m.p. 172-173 ° C; MS The m / e 397 (M +). Elemental analysis for C 18 H 18 F 3 N 3 O 4: Calculated: C, 54.41; H, 4.57; N, 10.58 Found: C, 54.34; H, 4.33; N, 10.53 3c N- [3- (2-Amino-3-nitro-phenoxy) -propyl] -N-benzyl-2,2,2-trifluoroacetamide as a yellow solid (67.8%), m.p. 92.93 ° C; MS The m / e 397 (M +). Elemental analysis for C 18 H 18 F 3 N 3 O 4: Calculated: C, 54.41; H, 4.57; N, 10.58 Found: C, 54.30; H, 4.50; N, 10.50 3d N- [2- (2-amino-3-ni tro-phenoxy) -ethyl] -2,2,2-trifluoro-N-na talen-1-ylmethyl-acetamide as a yellowish-orange colored solid (75.3 %), pf 133-135 ° C; MS M / e 433 (M +). Elemental analysis for C2? Hi8F3N304: Calculated: C, 58.20; H, 4.19; N, 9.70 Found: C, 58.28; H, 4.07; N, 9.48 3e N- [2- (2-Amino-3-nitro-phenoxy) -ethyl] -N- (4-tert-butyl-benzyl) -2,2,2-tri-luoroacetamide as a yellow solid (82.0%) ), pf 80-82 ° C; MS The m / e 439 (M +). Elemental analysis for C2? H24F3N3? 4: Calculated: C, 57.40; H, 5.51; N, 9.56 Found: C, 57.09; H, 5.31; N, 9.40 3f N- [2- (2-amino-3-nitro-phenoxy) -ethyl] -2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide as a yellow solid (77.4%), m.p. 143-144 ° C; MS The m / e 389 (M +). Elemental analysis for Ci5Hi4F3N304S: Calculated: C, 46.27; H, 3.62; N, 10.79 Found: C, 46.19; H, 3.39; N, 10.64 3g N- [2- (2-Amino-3-ni tro-phenoxy) -ethyl] -N- (4-chloro-benzyl) -2,2,2-trifluoroacetamide as a yellow solid (84.0%), pf 138-139 ° C; MS (+) BAR m / e 418/420 (M + H +). Elemental analysis for C? 7H? 5ClF3N304: Calculated: C, 48.88; H, 3.62; N, 10.06 Found: C, 48.66; H, 3.47; N, 9.82 3h_ N- [2- (2-Amino-5-chloro-3-nor tro-phenoxy) -ethyl] -N-benzyl-2,2,2-trifluoroacetamide as a solid yellow (67.9%), p.f. 106-108 ° C; EM (+) BAR m / e 418/420 (M + H +). Elemental analysis for C17H15CIF3N3O4: Calculated: C, 48.88; H, 3.62; N, 10.06 Found: C, 48.96; H, 3.50; N, 10.03 3i N- [2- (2 -Ami non-5-chloro or -3-nitro-f-enoxy) -ethyl] -2,2,2-trifluoro-N-thiof en-2-ylmethyl-acetamide as a yellow solid (59.6%), mp 97-98 ° C; EM The m / e 423/425 (M +). Elemental analysis for C15H13CIF3N3O4S: Calculated: C, 42.51; H, 3.09; N, 9.92 Found: C, 42.37; H, 2.97; N, 9.84 3j N- [2- (2-amino-S-chloro-3-ni tro-enoxy) -ethyl] -2,2,2-trifluoro-N-thio en-3-ylmethyl-acetamide as a yellow solid (80.0 %), pf 149-150 ° C; EM The m / e 423/425 (Mt Elemental analysis for C15H13CIF3N3O4S: Calculated: C, 42.51; H, 3.09; N, 9.92 Found: C, 42.02; H, 2.95; N, 9.7: 3k N- [2- (2-amino-3-nitro-phenoxy) -ethyl] -2,2,2-trifluoro-N- (3-phenyl-propyl) -acetamide as a yellow solid (72.6%), m.p. 81-82 ° C; EM The m / e All (M +).

Elemental analysis for Ci9H2oF3N3? 4: Calculated: C, 55.47; H, 4.90; N, 10.21 Found: C, 55.57; H, 4.66; N, 10.23 Intermediate 4a N-Benzyl-N- [2- (2, 3-di ami o-f-enoxy) -ethyl] -2, 2, 2-tri-luoroacetamide To a mixture of N- [2- (2-amino -3-nitro-phenoxy) -ethyl] -N-benzyl-2,2,2-trifluoro-acetamide (3a, 2.4 g, 6.26 mmol) and palladium on carbon at 10% (0.40 g) in ethanol (200 ml) at 50-55 ° C was added a solution of hydrazine hydrate (2.0 g) in ethanol (25 mi). The reaction was allowed to stir for 18 hours at 23 ° C, then the catalyst was filtered through solka floc and the solvent was removed under vacuum to provide 1.96 g (88.9%) of an amber oil. Crystallization from ethyl acetate-hexane gave a white solid, m.p. 118-119 ° C; EM (+) BAR m / e 354 (M + H +). Elemental analysis for Ci7H18F3N3? 2: Calculated: C, 56.58; H, 4.72; N, 12.38 Found: C, 57.49; H, 5.10; N, 11.86 Following the procedure above and using N- [2- (2-amino-3-nitro-phenoxy) -ethyl] -2,2,2-trifluoro-N- (4-methyl-benzyl) acetamide, N - [3- (2-amino- 3-nitro-phenoxy) -propyl] -N-benzyl-2,2,2-trifluoroacetamide, N- [2- (2-amino-3-nitrophenoxy) -ethyl]] - 2, 2, 2-trifluoro-N-naphthalen-1-ylmethyl-acetamide, N- [2- (2-amino-3-nitro-phenoxy) -ethyl] -N- (4-tert-butyl-benzyl) -2, 2, 2, -trifluoro-acetamide, N- [2- (2-amino-3-nor tro-phenoxy) -ethyl] -2, 2, 2, -trifluoro-N-thiophen-2-ylmethyl-acetamide, N- [ 2- (2-amino-3-nitro-phenoxy) -ethyl] -N- (4-chloro-benzyl) -2,2,2-trifluoro-acetamide, N- [2- (2-amino-5-chloro -3-nitro-phenoxy) -ethyl] -N-benzyl -2, 2, 2-trifluoro-acetamide, N- [2- (2-amino-5-chloro-3-nitro-phenoxy) -ethyl] -2 , 2, 2-tri-fluoro-N-thiophen-2-ylmethyl-acetamide and N- [2- (2-amino-5-chloro-3-nitro-phenoxy) -ethyl] -2, 2, 2, -trifluoro-N-thiophen-3-ylmet i 1-acetamide gave respectively: 4b N- [2- (2, 3-Diamino-phenoxy) -ethyl] -2,2,2-trifluoro-N- (4-methyl-benzyl) -acetamide as a white solid (85.0%), m.p. 94-96 ° C; MS The m / e 367 (M +). Elemental analysis for C 18 H 20 F 3 N 3 O 2: Calculated: C, 58.85; H, 5.49; N, 11.44 Found: C, 58.91; H, 5.32; N, 11.45 4c N-Benzyl-N- [3- (2, 3-diamino-phenoxy) propyl] -2,2,2-trifluoroacetamide as a white solid (86.5%), m.p. 56-58 ° C; MS The m / e 367 (M +).

Elemental analysis for C? 8H2? F3N302: Calculated: C, 58.85; H, 5.49; N, 11.44 Found: C, 59.00; H, 5.42; N, 11.4: 4d N- [2- (2, 3-Diamino-enoxi) -ethyl] -2, 2, 2-tri luor or -N-na talen-1-ylmethyl-acetamide as a viscous yellow oil (63.0%); MS (+) BAR m / e 404 (M + H +). Elemental analysis for C2? H2OF3N302: Calculated: C, 62.53; H, 5.00; N, 10.42 Found: C, 62.45; H, 4.98; N, 10.20 4e N- (4-tert-Butyl-benzyl) -N- [2- (2, 3-diami-phenoxy) -ethyl] -2, 2, 2-tri-luoroacetamide as a viscous brown oil (72.7% ); MS El / e 409 (M +). 4f N- [2- (2, 3-Diamino-phenoxy) -ethyl] -2, 2, 2-trifluoro-N-thiophen-2-ylmethyl-acetamide as a white solid (41.0%), m.p. 72-74 ° C; MS (+) BAR m / e 404 (M + H +). Elemental analysis for C? 5H? 6F3N302S: Calculated: C, 50.13; H, 4.49; N, 11.69 Found: C, 50.09; H, 4.38; N, 11.59 4g N- (-chloro-benzyl) -N- [2- (2, 3-diamino-enoxy) -ethyl] -2, 2, 2-trifluoroacetamide as a brown oil (80.9%), MS m / e 387/389 (M +).

Elementary analysis for : Calculated: C, 52.65; H, 4.42; N, 10.84 Found: C, 52.47; H, 4.51; N, 10.60 4h N-Benzyl-N- [2- (2, 3-di ami non-5-chloro-f-enoxy) -ethyl] -2,2,2-tri-luoroacetamide as a viscous brown oil (76.2%); EM The m / e 387/389 (M *). Elemental analysis for CI-GHÍ-C1F3N302: Calculated: C, 52.65; H, 4.42; N, 10.84 Found: C, 52.47; H, 4.39; N, 10.90 4i N- [2- (2, 3-Diamino-5-chloro-enoxy) -ethyl] -2,2,2-tri luoro-N-thio en-2-ylmethyl-acetamide as a viscous brown oil (71.4% ); EM The m / e 393/395 (M +). Elemental Analysis for Ci5Hi5ClF3N302S: Calculated: C, 45.75; H, 3.84; N, 10.67 Found: C, 45.58; H, 3.93; N, 10.64 4 j N- [2- (2, 3-Diamino-5-chloro-enoxy) -ethyl] -2,2,2-trifluoro-N-thiof en-3-ylmethyl-acetamide as a viscous brown oil (75.0 %); EM The m / e 393/395 (M +). Elemental Analysis for C? 5Hi5ClF3N302S: Calculated: C, 45.75; H, 3.84; N, 10.67 Found: C, 45.39; H, 3.84; N, 10.56 Intermediate 5a -Benzyl -2, 2, 2-trifluoro-N- [2- (2-oxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] acetamide A mixture of N-benzyl-N- [2- (2, 3-diamino-phenoxy) -ethyl] -2,2,2-trifluoroacetamide (0.28 g, 0.804 mmol) and diimidazole carbonyl (0.326 g, 2.0 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at 23 ° C for 2 hours. The reaction was poured into water and extracted with ethyl acetate (2 x 150 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under vacuum. Purification by chromatography (60 g of silica gel, ethyl acetate: hexane: 2 M NH 3 in methanol (15: 5: 1)) afforded 0.29 g (94.8%) of a colorless oil. Crystallization of hexane gave a white solid, m.p. 121-123 ° C; MS M / e 379 (M +). Elemental analysis for C18H16F3N303: Calculated: C, 56.99; H, 4.25; N, 11.08 Found: C, 57.09; H, 4.07; N, 11.10 Using N- [2- (2, 3-diamino-phenoxy) -ethyl] -2,2,2-trifluoro-N- (-met i 1 -benzyl) -acetamide, N-benzyl-N- [ 3- (2,3-di-amino-phenoxy) -propyl] -2,2,2-trifluoro-acetamide, N- [2- (2, 3-diamino-phenoxy) -ethyl] -2,2, 2- trifluoro-N-naphthal en-1-lmethyl-1-acetamide, N- (4-tert-butyl-benzyl-N- [2- (2, 3-diamino-phenoxy) -ethyl] - 2,2, 2-trifluoroacetamide, N- [2- (2, 3-diamino-phenoxy) -ethyl] -2, 2, 2-trifluoro-N-thiophen-2-ylmethyl-acetamide, N- (4 -chloro-benzyl) -N- [2- (2, 3-diamino-phenoxy) -ethyl] -2,2, 2-trifluoro-acetamide, N-benzyl-N- [2- (2,3-diamino- 5-chloro-phenoxy) -ethoxy] -2, 2, 2-tri-fluoro-acetamide, N- [2- (2,3-diamino-5-chlorophenoxy) -ethyl] -2,2, 2-trifluoro -N-thiophen-2-ylmethyl-acetamide and N- [2- (2, 3-diamino-5-chloro-phenoxy) -ethyl] -2, 2, 2-trifluoro-N-thiophen-3-ylmethyl-acetamide in the general procedure above, respectively: 5b 2, 2, 2 -Trifluoro-N- (4-methyl-benzyl) -N- [2- (2-oxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -acetamide • 0.1 of ethyl acetate as a white solid (96.6%), mp 194-196 ° C; MS (+) BAR m / e 394 (M + H +). Elemental analysis for C? 9Hi8F3N303 »0.1 C4H802 Calculated: C, 57.94; H, 4.71; N, 10.45 Found: C, 58.90; H, 4.60; N, 10.19 5c N-Benzyl-2, 2, 2-tri luoro-N- [3- (2-oxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -propyl] -acetamide as a white solid (86.0%) ), pf 114-116 ° C; MS (+) BAR m / e 394 (M + H *).

Elemental analysis for C 5 H 16 F 3 N 303: Calculated: C, 58.01; H, 4.61; N, 10.68 Found: C, 57.67; H, 4.37; N, 10.49 5d 2,2,2-Trifluoro-N-naphthalen-l-ylmethyl-N- [2- (2-oxo-2,3-dihydro-lH-benzimidazol-4-yloxy) -ethyl] acetamide as a solid white (90.0%), mp 88-90 ° C; MS M / e 429 (M +). Elemental analysis for C22H? 8F3N303 Calculated: C, 61.54; H, 4.23; N, 9.79 Found: C, 61.34; H, 4.25; N, 9.52 5e N- (4-tert-Butyl-benzyl) -2,2, 2-trifluoro-N- [2- (2-oxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -acetamide as a white solid (84.9%), mp 184-185 ° C; EM The m / e 435 (M ~). Elemental analysis for C22H24F3N303 Calculated: C, 60.68; H, 5.55; N, 9.65 Found: C, 60.59; H, 5.55; N, 9.66 5_f 2,2,2-Trifluoro-N- [2- (2-oxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -N-thiophen-2-ylmethyl-acetamide as a white solid (73.3%), pf 49-50 ° C; MS The m / e 385 (M +). 5g N- (4-Chloro-benzyl) -2,2, 2-trifluoro-N- [2- (2-oxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -acetamide as a white solid (56.7%), mp 190-192 ° C; MS (+) BAR m / e 414/416 (M +). Elemental analysis for C18H15CIF3N3O3 Calculated: C, 52.25: H, 3.65; N, 10.15 Found: C, 52.28; H, 3.55; N, 10.20 5h N-Benzyl-N- [2- (6-chloro-2-oxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -2,2,2-trifluoroacetamide as a white solid (60.0 %), pf 171-173 ° C; MS (+) APCI m / e 414.2 / 416.2 (M + H +). Elemental analysis for C? 8H? 5ClF3N3? 3 Calculated: C, 52.25; H, 3.65; N, 10.16 Found: C, 52.10; H, 3.56; N, 9.96 5i N- [2- (6-chloro-2-oxo-2,3-dihydro-lH-benzoimidazole '4-yloxy) -ethyl] -2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide as a white solid (70.1%), mp 153-154 ° C; EM The m / e 419/421 (M +). Elemental analysis for C? 6H13ClF3N303S: Calculated: C, 45.78; H, 3.12; N, 10.01 Found: C, 45.85; H; 3.02; N, 9.73 5j N- [2- (6-Chloro-2-oxo-2, 3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -2,2,2-tri-loo-N-thiophen-3-ylmethyl-acetamide as a white solid (77.8%), mp 152-153 ° C; EM The m / e 419/421 (M +). Elemental analysis for C? 6Hi3ClF3N3? 3S: Calculated: C, 45.78; H, 3.12; N, 10.01 Found: C, 45.86; H, 2.93; N, 9.76 Intermediate 6 N- [2- (2- { 2,2, 2-Trifluoroacetamidyl.} - 3-nor tro-phenoxy) -ethyl] -N-benzyl-2,2,2-trifluoroacetamide To a N- [2- (2-amino-3-ni-tro-phenoxy) -ethyl] -N-benzyl-2,2,2-trifluoroacetamide suspension (4.95 g, 12.9 mmol) in anhydrous methylene chloride (50 g. mi) at room temperature was added trifluoroacetic anhydride (3.18 g, 15.1 mmol). After 15 minutes, the reaction was diluted with ether and washed with saturated sodium bicarbonate (3x 80 ml) and the organic layer was dried over anhydrous magnesium sulfate. With filtration and evaporation of the solvent 5.84 g (94.4%) of a yellowish white solid, m.p. 114-115 ° C; EM BAR m / e 480 (M + H +). Elemental analysis for C19H15F6N3O5 Calculated: C, 47.61; H, 3.15; N, 8.77 Found: C, 47.35; H, 2.94; N, 8.69 Intermediate 7 N- [2- (l-Methyl-2- { 2,2,2-Trifluoroacetamidyl.} - 3-nitro-phenoxy) -ethyl] -N-benzyl-2,2,2-trifluoro- acetamide A suspension of potassium carbonate (1.44 g, 10.4 mmol), N- [2- (2-. {2, 2, 2-trifluoro-acetamidyl] -3-nitrophenol) -ethyl- N- Benzyl-2, 2, 2-trifluoroacetamide (1.0 g, 2.09 mmol) and methyl iodide (2.96 g, 20.9 mmol, previously filtered through basic alumina) in anhydrous dimethyl sulfoxide (11 mL) was allowed to stir at room temperature for 24 hours. The reaction mixture was poured into methylene chloride (200 ml) and extracted with water (2 x 80 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under vacuum to give a thick yellow oil. Purification by chromatography (30% ethyl acetate-hexanes) provided 960 mg (93.3%) of a light yellow solid, m.p. 90-92.5 ° C; MS m / e 493 (M +). Elemental analysis for C2oHi F6N3? 5 Calculated: C, 48.70; H, 3.47; N, 8.57 Found: C, 48.50; H, 3.27; N, 8.39 Intermediate 8 N-Benzyl-2- (2-methylamino-3-nitro-phenoxy) -ethylamine A suspension of potassium carbonate (2.52 g, 18.2 mmol) and N- [2-1-methyl- (2- {. 2, 2, 2-trifluoroacetamidyl.} - 3-nitro-phenoxy) -ethyl] -N-benzyl-2,2,2-trifluoroacetamide (900 mg, 1.82 mmol) in methanol-water (50 ml: 3 ml) was heated to reflux for 2 hours, then the solvent was evaporated and the residue was dissolved in methylene chloride (100 ml) and extracted with water (80 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under vacuum. The residue was further purified by passing it through a small pad of silica to provide 505 mg (92.1%) of N-benzyl-2- (Rethylamino-3-ni tro-phenoxy) ethylamine as a red oil; EM BAR m / e 302 (M + H +).

Intermediate 9 N-Benzyl- [2- (2-methylamino-3-ni-tro-phenoxy) -ethyl] -carbamic acid tert-butyl ester A solution of N-benzyl-2- (2-methylamino-3-nitro) phenoxy) -ethylamine (480 mg, 1.59 mmol) and di-tert-butyl dicarbonate (348 mg, 1.59 mmol) in anhydrous tetrahydrofuran (6 ml) was allowed to stir during 3 hours. The reaction mixture was poured into methylene chloride (80 ml) and washed with water (50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to provide 593 mg (93%) of an orange solid, m.p. 91-93 ° C; MS m / e 401 (M +). Elemental analysis for C2? H27N305 Calculated: C, 62.83; H, 6.78; N, 10.47 Found: C, 62.78; H, 6.53; N, 10.51 Intermediate 10 N-Benzyl- [2- (2-methylamino-3-amino-phenoxy) -ethyl] -carbamic acid-tert-butyl ester N-benzyl- [2- (2-methylamino-3-amino-phenoxy) -ethyl ester methylamino-3-nitrophenoxy) -ethyl] -carbamic acid (520 mg, 1.30 mmol) and 10% palladium on carbon (120 mg) in ethanol (40 ml) at 50 ° C was added a solution of hydrazine hydrate (1.3 g) in ethanol (10 ml). The reaction was allowed to stir for 3 hours, then the catalyst was filtered through celite and the solvent was removed. Purification by chromatography (30% ethyl acetate-hexane) gave 380 mg (78.9%) of a clear oil; MS The m / e (M +); IR (film) 3400, 3350, 1680 cm "1.

Intermediate 11 N-Benzyl- [2- (2-oxo-l, 3-dihydro-benzoimidazol-4-yloxy) -ethyl] -carbamic acid tert-butyl ester A mixture of N-benzyl-tert-butyl ester [2- (2-methylamino-3-amino-phenoxy) -ethyl] -carbamic acid (330 mg, 0.89 mmol) and diimidazole carbonyl (577 mg, 3.56 mmol) in anhydrous tetrahydrofuran (30 mL) was stirred at room temperature for 0.5 hours, and then heated to reflux for 3 hours. The reaction was poured into water and extracted with ethyl acetate (2 x 150 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed. Purification by chromatography (50% ethyl acetate-hexane) provided 268 mg (75.8%) of a foam; MS BAR m / e 398 (M + H +); IR (KBr) 3420, 3250, 1690 (sa) cpf1.

Intermediate 12 3- [2- (3,4-dihydro-lH-isoquinolin-2-yl) -ethoxy] -benzene-1,2-diamine The general procedure used in intermediate 4 using 2- [2- (3, 4-dihydro-lH-isoquinolin-2-yl) -ethoxy] -6-nitrophenylamine (2k) gave 3- [2- (3,4-dihydro-lH-isoquinolin-2-yl) -ethoxy] - benzene, 2-diamine as a solid (95%), mp 76-77 ° C. This material was characterized as the dihydrochloride salt 0.4 H20; EM The m / e 283 (M ~). Elemental analysis for C? 7H21N30"2 HC1" 0.4 H20: Calculated: C, 56.17; H, 6.60; N, 11.56 Found: C, 56.15; H, 6.68; N, 11.25 Intermediate 13 4-Chloro-2- (2-chloro-ethoxy) -6-nor ro-phenylamine A solution of 2- (2-chloro-ethoxy) -6-nitrophenylamine (la, 30.0 g, 0.14 moles) , N-chlorosuccinamide and acetonitrile (1.3 1) was heated at reflux for 4 hours. The mixture was concentrated under vacuum and the residue was diluted with ethyl acetate (500 ml). The organic layer was washed with water (2X, 250 ml) and saline (250 ml), dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under vacuum to give an orange solid residue. Crystallization from ethyl acetate-hexane gave 33.5 g (95.3%) as an orange solid, m.p. 109-110 ° C; EM The m / e 250/252/254 (M +). Elemental analysis for C8H8C12N203: Calculated: C, 38.27; H, 3.21; N, 11.16 Found: C, 38.15; H, 3.10; N, 10.96 Example 1 4- (2-Benzylamino-ethoxy) -1, 3-dihydro-benzoimidazol-2-one A suspension of potassium carbonate (1.15 g, 8.34 mmol) and N-benzyl-2,2,2-trifluoro-N - [2- (2-Oxo-l, 3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -acetamide (0.38 g, 1.00 mmol) in methanol-water (30 ml: 2 ml) was heated at reflux for 2 h, then the solvent was evaporated and the residue was dissolved in ethyl acetate (100 ml) and extracted with water (80 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under vacuum to give the title compound as a white solid, m.p. 132-135 ° C. Without further purification, this material was dissolved in ethyl acetate-methanol (1: 1) and treated with an excess amount of 1N HCl in ether to provide 0.30 g (75.0%) of the hydrochloride salt as a solid color light cinnamon, pf 230-233 ° C; MS The m / e 283 (M +). Elemental analysis for C? 6H? 7N302.HCl Calculated: C, 60.09; H, 5.67; N, 13.14 Found: C, 59.84; H, 5.59; N, 12.92 Example 2 4- [2- (4-Methyl-benzylamino) -ethoxy] -1,3-dihydrobenzoimidazol-2-one Following the general procedure used in Example 1, and using 2, 2, 2-trifluoro-N - (-methyl-benzyl) -N- [2- (2-oxo-2,3-dihydro-lH-benzimidazl-4-yloxy) -ethyl] -acetamide «0.1 ethyl acetate (5b) the compound of the title as a white solid (64.5%), mp 162-163 ° C; MS (+) BAR m / e 298 (M + H +). Treatment of the free base with ethereal HCl gave a white solid (90.0%), m.p. 244-246 ° C; MS (+) BAR m / e 298 (M + H +). Elemental analysis for Ci7H19N302 «l.0 HC1 * 1.7 H20 Calculated: C, 56.17; H, 6.46; N, 11.56 Found: C, 55.94; H, 6.05; N, 11.42 Example 3 4 (7) - (2-benzylamino-ethoxy) -1- (3) -methyl-1,3-dihydrobenzoimidazol-2-one To a solution of N-benzyl- [2-tert-butyl ester] - (2-Oxo-l, 3-dihydro-benzoimidazol-4-yloxy) -ethyl] -carbamic acid in anhydrous methylene chloride (7 ml) was added trifluoroacetic acid (3 ml). After 15 minutes, the reaction was poured into saturated aqueous sodium bicarbonate (150 ml) and extracted with methylene chloride (2 x 150 mL). The organic layer was dried and the solvent was removed to provide 170 mg (87%) of a white solid; p.f. 137-138 ° C; EM BAR 298 (M + H +). The fumarate salt was prepared by adding a solution of the free base (165 mg) in warm isopropanol (15 ml) to an excess of fumaric acid in warm isopropanol (20 ml). Upon completion of the addition the crystals were started to form, and the mixture was allowed to cool to room temperature, and the crystals were filtered to provide 203 mg of fumarate salt, m.p. 201.5-202.5 ° C; ESI MS m / e 298 (M + H +). Elemental analysis for Ci H? 9N3? 2 »C4H? 4 Calculated: C, 61.01; H, 5.61; N, 10.16 Found: C, 60.73; H, 5.36; N, 9.95 Example 4 4- (3-Benzylamino-propoxy) -1,3-dihydro-benzoimidazol-2-one Following the general procedure used in Example 1, and using N-benzyl-2,2,2-trifluoro-N- [ 3- (2-Oxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -propyl] -acetamide (5c) the title compound was obtained as a light yellow solid foam (90.4%); MS The m / e 297 (M +). The treatment of free base with ethereal HCl provided the hydrochloride salt as a white solid (63.9%), m.p. 243-244 ° C: MS m / e 297 (M +). Elemental analysis for C? 7H? 9N3? 2 # HCl: Calculated: C, 61.7; H, 6.04; N, 12.59 Found: C, 60.92; H, 5.95; N, 12.41 Example 5 4-. { 2- [(Naf talen-1-ylmethyl) -ami no] -ethoxy} -1,3-dihydro-benzoimidazol-2-one Following the general procedure used in Example 1, and using 2, 2, 2-trifluoro-N-naphthalen-1-ylmethyl-N- [2- (2-oxo -2,3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -acetamide (5d) the title compound was obtained as a white solid (67.4%); MS The m / e 333 (M +). Elemental analysis for C2oH19N302: Calculated: C, 72.05; H, 5.74; N, 12.60 Found: C, 71.72; H; 5.76; N, 12.22 Treatment of the free base with ethereal HCl gave the quarter HCl hydrate as a white solid (63.9%), m.p. 223-225 ° C: MS m / e 333 (M +). Elemental analysis for C? 7H? 9N3? 2 «HCl * hydrate room: Calculated: C, 64.17; H, 5.52; N, 11.23 Found: C, 64.33; H, 5.42; N, 11.28 Example 6 4- [2- (4-tert-Butyl-benzylamino) -ethoxy] -1,3-dihydrobenzoimidazol-2-one Following the general procedure used in Example 1, and using N- (4-ter) -but il-benzyl) -2, 2, 2-trifluoro-N- [2- (2-oxo-2,3-dihydro-lH-benzoimidazl-4-yloxy) -ethyl] -acetamide (5_e) was obtained compound of the title as a white solid (84.5%); MS M / e 339 (M +). Elemental analysis for C2oH25N302: Calculated: C, 70.77; H; 7.42; N, 12.38 Found: C, 70.59; H, 7.44; N, 12.28 Treatment of the title compound with ethereal HCl gave the hemihydrated HCl salt as a white solid m.p. 224-226 ° C: MS m / e 339 (M +). Elemental analysis for C2oH25N302 # HCl »hemihydrate: Calculated: C, 62.41; H, 7.07; N, 10.92 Found: C, 62.64; H, 6.93; N, 10.88 Example 7 4-. { 2- [(Thiophen-2-ylmethyl) -amino] -ethoxy} -1, 3-dihydrobenzoimidazol-2-one Following the general procedure used in example 1, and using 2, 2, 2-trifluoro-N- [2- (2-OXO-2,3-dihydro-lH- benzoimidazol-4-yloxy) -ethyl] -N- thiophen-2-ylmethyl-acetamide (5_f) the title compound was obtained as a white solid (76.8%); MS The m / e 289 (M +). Elemental analysis for Ci4H15N302S: Calculated: C, 56.36; H, 5.41; N, 14.08 Found: C, 56.42; H, 5.04; N, 14.21 Conversion of the free base to the HCl salt with ethereal HCl gave a white solid of m.p. 240-241 ° C: MS m / e 289 (Mt). Elemental analysis for Ci H? 5N302S * HCl: Calculated: C, 51.61; H, 4.95; N, 12.90 Found: C, 51.22; H, 4.82; N, 12.70 Example 8 4- [2- (4-Chloro-benzylamino) -ethoxy] -1,3-dihydrobenzoimidazol-2-one Following the general procedure used in Example 1, and using N- (4-chloro-benzyl) -2, 2, 2-trifluoro-N- [2- (2-oxo-2,3-dihydro-H-benzoimidazol-4-yloxy) -ethyl] -acetamide (5_c) the title compound was obtained as a solid white (77.6%); p.f. 163-164 ° C; MS (+) BAR m / e 318/320 (M + H +). Elemental analysis for c? 6H? 6ClN302: Calculated: C, 60.48; H, 5.08; N, 13.22 Found: C, 60.17; H, 4.83; N, 13.20 Treatment of the free base with ethereal HCl provided the hydrochloride as a white solid, of m.p. > 250: EM The m / e 317/319 (M +). Elemental analysis for Ci6Hi6Cl302 # HCl: Calculated: C, 54.25; H, 4.84; N, 11.86 Found: C, 54.18; H, 4.76; N, 11.87 Example 9 4- (2-Benzylamino-ethoxy) -6-chloro-l, 3-dihydrobenzoimidazol-2-one Following the general procedure used in Example 1, and using N- (4-chloro-benzyl) -2 , 2, 2-trifluoro-N- [2- (6-chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy) -ethyl] -acetamide (5_h) the title compound was obtained as a white solid (77.6%), mp 192-193 ° C; EM The m / e 317/319 (M +). Elemental analysis for C? 6H? 6ClN302: Calculated: C, 60.48; H, 5.08; N, 13.22 Found: C, 60.24; H, 5.01; N, 13.09 Treatment of the free base with ethereal HCl provided the hydrochloride salt as a white solid, of m.p. > 250 ° C: MS The m / e 317/319 (M +). Elemental analysis for Ci6H? 6ClN302 »lHCl: Calculated: C, 54.25; H, 4.84; N, 11.86 Found: C, 54.23; H, 4.85; N, 11.69 Example 10 6-Chloro-4-. { 2- [(thio en-2-ylmethyl) -amino] -ethoxy} -1, 3- dihydro-benzoimidazol-2-one Following the general procedure used in Example 1, and using N- [2- (6-chloro-2-oxo-2,3-dihydro-lH-benzoimidazole-4-) iloxy) -ethyl] -2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide (5_i) the title compound was obtained as a white solid (89.0%), mp 179-180 ° C; MS M / e 323-325 (M +). Elemental analysis for C14H14CIN3O2S: Calculated: C, 51.93; H, 4.36; N, 12.98 Found: C, 51.80; H, 4.23; N, 12.96 Treatment of the title compound with ethereal HCl afforded the hydrochloride as a white solid (90%), m.p. > 250 ° C: MS The m / e 323/325 (M +). Elemental Analysis for Ci Hi4ClN302S * HCl: Calculated: C, 46.68; H, 4.20; N, 11.66 Found: C, 46.52; H, 4.00; N, 11.57 Example 11 6-Chloro-4-. { 2- [(thiophen-3-ylmethyl) -amino] -ethoxy} -1, 3- dihydro-benzoimidazol-2-one Following the general procedure- used in example 1, and using N- f 2- (6-chloro-2-oxo-2,3-dihydro-lH-benzoimidazole-4) -iloxy) -ethyl] -2,2,2- trifluoro-N-thiophen-3-ylmethyl-acetamide (5j_) the title compound was obtained as a white solid (89.0%), m.p. 182-183 ° C; MS (+) BAR m / e 324/326 (M + Ht). Elemental Analysis for C14Hi4ClN302S: Calculated: C, 51.93; H, 4.36; N, 12.98 Found: C, 51.96; H, 4.30; N, 12.95 The title compound was treated with ethereal HCl to obtain the hydrochloride salt as a white solid (90.0%), m.p. > 250 ° C: MS The m / e 323/325 (M +). Elemental analysis for C? 4H? 4ClN302S * HCl: Calculated: C, 46.68; H, 4.20; N, 11.66 Found: C, 46.29; H, 4.09; N, 11.51 Example 12 4- [2- (2, 3-dihydro-lH-isoquinolin-2-yl) -ethoxy] -1,3-dihydro-benzoimidazol-2-one Following the general procedure used in Example 1, and using 2 - [2- (3, 4-dihydro-lH-isoquinolin-2-yl) -ethoxy] -6-nitro-phenylamine (2k) the title compound was obtained as a white solid (63.0%), mp. 173-174 ° C; MS The m / e 309 (M +). Elemental analysis for C? 8H? 9N302: Calculated: C, 69.88; H, 6.19; N, 13.58 Found: C, 69.48; H, 6.01; N, 13.55 Treatment of the free base with ethereal HCl gave a quarter hydrate of the hydrochloride salt as a white solid (90.0%), m.p. > 250 ° C: MS The m / e 323/325 (M +). Elemental analysis for C? 8H19N3O »HCl * 0.25 H20: Calculated: C, 61.71; H, 5.90; N, 11.99 Found: C, 61.90; H, 5.88; N, 11.97 Example 13 4- [2- (3-Phenyl-propylamine) -ethoxy] -1,3-dihydrobenzoimidazol-2-one Following the general procedures used in intermediates 4 and 5 and Example 5, the N- [2 - (2-amino-3-nitro-phenoxy) -ethyl] -2,2,2-trifluoro-N- (3-phenyl-propyl) -acetamide (3k) gave the title compound as a white solid; MS (+) BAR m / e 312 (M + H +). Elemental analysis for C? 8H2? N3O2 «0.5H20: Calculated: C, 67.48; H, 6.92; N, 13.12 Found: C, 67.81; H, 6.76; N, 13.51 Treatment of the free base with ethereal HCl afforded the hydrochloride salt as a white solid (90.9%), m.p. 243-145 ° C: MS (+) BAR m / e 312 (M + H +).

Elemental analysis for C? SH2: N302 # HCl: Calculated: C, 62.15; H, 6.38; N, 12.08 Found: C, 62.06; H, 6.21; N, 11.97 Pharmacology A method for determining the intrinsic activity in the dopamine D2 receptor was recently reported [Lahti et al., Mol. Pharm., 42, 432-438, (1993)]. Intrinsic activity is predicted using the ratio of the "low affinity agonist" (LowAg) state of the receptor to the high affinity (HighAg) receptor state, ie, LowAg / HighAg. These relationships correlate with the activity of agonist, partial agonist, and antagonist of a given compound, the activities characterize the ability of the compound to produce an anti-psychotic effect.The affinity for dopamine self-receptor was established by a modification of the standard experimental test procedure of Seemen and Schaus , European Journal of Pharmacology 203: 105-109, 1991, where rat striatum brain tissue homogenized with 3 H-quinpirole (Quin.) And various concentrations of the test compound is incubated, filtered, it is washed and counted in a Betaplate scintillation counter. The high affinity for the D-2 dopamine receptor was established by the standard experimental test procedure of Fields, et al., Brain Res., 136, 578 (1977) and Yamamura et al., Editors, Neurotransmitter Receptor Binding, Raven Press , NY (1978) where limbic brain tissue homogenized with JH-Spiroperidol (Spiper.) And various concentrations of the test compound are incubated, filtered and washed and shaken with a Hydrofluor scintillation cocktail (National Diagnostics) and counted in a Packard 460 CD scintillation counter. The results of the tests with the representative compounds of this invention are given in the following table immediately.

Pharmaceutical Compositions The compounds of this invention can be administered without mixing or with a pharmaceutical carrier to a patient in need thereof. The pharmaceutical carrier can be solid or liquid. Applicable solid carriers can be to include one or more or substances that can also act as flavoring agents, lubricants, stabilizers, suspending agents, fillers, slip aids, compression aids, binders or tablet disintegrating agents or an encapsulating material. In the powders, the carrier is a finely divided solid, which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting point waxes, and ion exchange resins. Liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. acceptable The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives such as those above, for example, cellulose derivatives, preferably a solution of sodium carboxymethylcellulose) alcohols (including monohydric alcohols and polyhydric alcohols, example, glycols), and its derivatives and oils (for example, fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in compositions in sterile liquid form for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used for example by intramuscular, intraperitoneal or subcutaneous injection. The solutions Sterile can also be administered intravenously. Oral administration can be either a liquid or a solid dosage form. The compounds of this invention can be administered rectally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation, or insufflation, the compounds of this invention can be formulated in an aqueous or partially aqueous solution., which can then be used in the form of an aerosol. The compounds of this invention can also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows the delivery of the agent for absorption. systemic in the bloodstream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be liquid or semisolid viscous emulsions of either the oil in water type or the water in oil type. Pastes comprising absorptive powders dispersed in petrolatum or hydrophilic petrolatum containing the Active ingredient may also be suitable. A variety of occlusive devices can be used to release the active ingredient into the bloodstream, such as a semipermeable membrane that covers a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature. The dosage that is to be used in the treatment of a specific patient suffering from a dopamine imbalance must be determined subjectively by the attending physician. The variables involved include the severity of the dysfunction and the size, age, and response pattern of the patient. The treatment will generally begin with small dosages less than the optical dose of the compound. After this, the dose is increased until the optimum effect is reached under the circumstances. The precise dosages for oral, parenteral, nasal or intrabronchial administration will be determined by the attending physician based on experience with the individual subject treated and the standard medical principles.

Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets or capsules. In such form, the composition is sub-divided into unit dose containing appropriate quantities of the active ingredient; the unit dosage form can be of packaged compositions, for example packaged powders, vials, ampoules, pre-filled syringes or sachets containing liquids. The unit dosage form may be, for example, a capsule or tablet thereof, or it may be the appropriate number of any of the compositions in package form. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound that has the formula characterized in that; R1 is hydrogen or alkyl of 1 to 6 carbon atoms; R 2 is selected from hydrogen, straight or branched chain 1 to 10 carbon atoms, cyclohexylmethyl or - (CH 2) mAr wherein Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents independently selected from alkyl of 1 to 6 carbon atoms, halogen, alkoxide of 1 to 6 carbon atoms and trifluoromethyl; or NR1R2 is 1, 2, 3, 4-tetrahydroquinolin-1-yl or 1,2,3,4-tetrahydroisoquinolin-2-ylo; m is 1 - 5; n e s 1 or 2; R3 is hydrogen or alkyl of 1 to 6 carbon atoms; Y is halogen, alkyl of 1 to 6 carbon atoms, and alkoxy of 1 to 6 carbon atoms; and the pharmaceutically acceptable salts thereof

2. A compound according to claim 1, characterized in that it is 4- (2-benzylamino-ethoxy) -1,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1, characterized in that it is 4- [2- (4-methyl-benzylamino) -ethoxy] -1,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1, characterized in that it is 4 (7) - (2- benzylamino-ethoxy) -1- (3) -methyl-1,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1, characterized in that it is 4- (3-benzylamino-propoxy) -1,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1, characterized in that it is 4 { 2- [(naphthalen-1-ylmethyl) -amino] -ethoxy} -l, 3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

7 A compound according to claim 1, characterized in that it is 4 - [2- (4-tert-butyl-benzylamino) -ethoxy] -1,3-dihydro-benzoimidazo-l-2-one or a pharmaceutically acceptable salt e of the same.

8. A compound according to claim 1, characterized in that it is 4-. { 2- [(thiophen-2-ylmethyl) -amino] -ethoxy} - !, 3-dihydro- benzoimidazo1-2-one a pharmaceutically acceptable salt thereof

9. A compound according to claim 1, characterized in that it is 4- [2- (4-chloro-benzylamino) -ethoxy] -1,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 1, characterized in that it is 4- (2-benzylamino-ethoxy) -6-chloro-l, 3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1, characterized in that it is 6-Chloro-4-. { 2- [(thiophen-2-ylmethyl) -amino] -ethoxy} -l, 3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1, characterized in that it is 6-Chloro-4-. { 2- [(thiophen-3-ylmethyl) -amino] -ethoxy} - !, 3-dihydro- benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 1, characterized in that it is 4- [2- (2,3-Dihydro-lH-isoquinolin-2-yl) -ethoxy} -l, 3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

14. A compound according to claim 1, characterized in that it is 4- (2-benzylamino-ethoxy) -1,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

15. Use of a compound of the formula. wherein R1 is hydrogen or alkyl of 1 to 6 carbon atoms; R 2 is selected from hydrogen, straight or branched chain alkyl of 1 to 10 carbon atoms, cyclohexylmethyl or - (CH 2) pA.r wherein Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents independently selected from alkyl of 1 to 6 carbon atoms, halogen, alkoxide of 1 to 6 carbon atoms and trifluoromethyl; or NRR2 is 1, 2, 3, 4-tetrahydroquinolin-1-yl or 1,2,3,4-tetrahydroisoquinolin-2-yl; 10 is 1-5; n is 1 or 2; R3 is hydrogen or alkyl of 1 to 6 carbon atoms; Y is halogen, alkyl of 1 to 6 carbon atoms, and alkoxy of 1 to 6 carbon atoms; twenty and pharmaceutically acceptable salts thereof for the preparation of a medicament for treating diseases in a mammal, which reacts to treatment by the administration of a dopamine D "agonist.

16. The use in accordance with the claim 15, characterized in that the disease treated is schizophrenia.

17. The use according to claim 15, characterized in that the disease treated is the Parkinson's disease.

18. The use of coformity with claim 15, characterized in that the disease treated is Tourette's syndrome.

19. The use according to claim 15, characterized in that the disease treated is the drug addiction to alcohol.

20. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to the formula wherein: R1 is hydrogen or alkyl of 1 to 6 carbon atoms; R 2 is selected from hydrogen, straight or branched chain 1 to 10 carbon atoms, cyclohexylmethyl or - (CH 2) mAr wherein Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents independently selected from alkyl of 1 to 6 carbon atoms, halogen, alkoxide of 1 to 6 carbon atoms and trifluoromethyl; or NRXR2 is 1, 2, 3, 4-tetrahydroquinolin-1-yl or 1, 2,3,4-tetrahydroisoquinolin-2-yl; m is 1-5; n is 1 or 2; R3 is hydrogen or alkyl of 1 to 6 carbon atoms; Y is halogen, alkyl of 1 to 6 carbon atoms, and alkoxy of 1 to 6 carbon atoms; and the pharmaceutically acceptable salts thereof