MXPA99007587A - 4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-thiones derivatives, their preparation and their use as dopamine autoreceptor (d2) agonists - Google Patents

Abstract

This invention relates to a novel series of compounds having potency at the dopamine D2 receptor which are illustrated by formula (I) wherein R1 is hydrogen or C1-C6 alkyl;R2 is hydrogen or C1-C6 alkyl;R3 is selected from hydrogen, straight-chain and branched alkyl group having up to 10 carbon atoms, 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 NR2R3 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;Y is halogen, C1-C6 alkyl, and C1-C6 alkoxy;or a pharmaceutically acceptable salt thereof.

Description

DERIVATIVES OF -AMINOALCOXI-1, 3-DIHYDROBENZOIMIDAZOL- 2-TIONAS, ITS PREPARATION AND ITS USE AS AGONISTS OF THE DOPAMINE AUTORRECEPTOR (D2) FIELD OF THE INVENTION The present invention relates to a novel series of compounds having power in the dopamine D2 receptor, which are illustrated by the following Formula I: I BACKGROUND OF THE INVENTION Efforts to induce anti-psychotic activity with dopamine autoreceptor agonists have been successful (Dorsini et al., Adv. Biochem. Psychopharmacol., 16, 645-648, 1977; Tamminga eta., Science, 200, 567-568; 1975; and Tamminga et al., Psy hiatry, 398-402, 1986). A method for determining the intrinsic activity in the D: receptor of dopamine was recently reported (Lahti et al., Mol. Pharm.

REF .: 30939 42, 432-438, 1993). Intrinsic activity is predicted using the ratio of the "low affinity agonist" state (LowAg) of the receptor and the "high affinity agonist" (HighAg) state of the receptor, i.e., LowAg / HighAg. These relationships correlate with the activities of agonist, partial agonist, and antagonist of a given compound, whose activities characterize the ability of a compound to produce an anti-psychotic effect. According to this invention, there is provided a group of compounds which are "useful anti-psychotic agents essentially free of extrapyramidal (EPS) side effects." The compounds of this invention are dopamine agonists with various degrees of intrinsic activity, some of which they are selective autoreceptor agonists, and therefore partial agonists (ie, active only autoreceptors against post-synaptic dopamine D2 receptors.) As such, they provide a functional modulation of the brain's dopamine systems without excessive blocking of the post-receptors. -synaptic dopamine which has been found to be responsible for the serious side effects exhibited frequently by agents that were otherwise clinically effective for the treatment of schizophrenia.Activation of dopamine autoreceptors results in a reduced neuronal discharge as well as well as the inhibition of the sis and dopamine release, and therefore provide a means to control 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, i.e., 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 possibly in the treatment of Parson's disease. A search- "in the literature indicated that a series of benzimidazol-2-ones were prepared as described in German patent 2700193. In particular, CGP-12177 (Ciba Geigy, shown below), was found to be a receptor antagonist. β-adrenergic [J. Biol. Chem., 258, 3496-3502, 1983].

CGP-12177 BRIEF DESCRIPTION OF THE INVENTION The compounds of the present invention are 4-aminoethoxy-l, 3-dihydro-benzoimidazole-2-thiones which are illustrated by Formula I: wherein R1 is hydrogen or alkyl of 1 to 6 carbon atoms; Rz is hydrogen or alkyl of 1 to 10 carbon atoms; R3 is selected from hydrogen, or a straight and branched chain alkyl group having up to 10 carbon atoms, cyclohexylmethyl or '-CH) mAr, wherein Ar is phenyl, naphthyl, thienyl, furanyl or pyridyl, each optionally substituted by one or two substituents independently selected from alkyl of 1 to 6 carbon atoms, halogen, alkoxy of 1 to 6 carbon atoms and trifluoromethyl; or NR K is 1, 2, 3, 4-tetrahydroquinolin-1-yl or 1,2,3-tetrahydroisoquinolin-2-yl; m is l-5; n is 1 or 2; And it is halogen, alkyl of 1 to 6 carbon atoms, and alkoxy of 1 to 6 carbon atoms; and the pharmaceutically acceptable salts thereof. The pharmaceutically acceptable acid addition salts have the utility of the free base. Such salts are prepared by methods well known in the art, they are formed as both inorganic and organic acids including, but not limited to, fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylene-salicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulphonic, hydrochloric, hydrobromic, sulfuric, cyclohexyl Faemic, phosphoric and nitric.

DETAILED DESCRIPTION OF THE INVENTION The compounds of Formula I are generally prepared by the general sequence indicated in the following Schemes I-III. Scheme I represents the synthesis of the compounds of the invention, wherein R 1 or R 2 is hydrogen.

Scheme II describes the synthesis of a compound of the invention, wherein none of R1 and R2 are hydrogen. Scheme Scheme III illustrates a route for obtaining a chlorinated Intermediate, which is used in the synthesis of a chlorinated compound of the invention.

Scheme III The following synthetic procedures for the intermediates and products of the invention are illustrated for illustrative purposes only, and should not be construed as limiting this description. Those skilled in the art of organic synthesis may be aware of other preparative methods for preparing the intermediates and compounds of the invention. The reagents and starting materials used are either commercially available or can be prepared according to standard procedures of the literature.

Intermediate la (n = l) 2- (2-Chloroethoxy) -6-ni tro-phenylamine 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) provided 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 moles) 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 +).

Intermediary Ib (n = 2) 2-. { 3-Bromo-propoxy) -6-nitro-phenylamine Following the procedure of method 2 above, and substituting 1,3-dibromopropane for 1,2-dichloroethane, the title compound was obtained as a yellow solid, (78.7%) pf 88-89 ° C; EM The m / e 274/276 (M +). Elementary analysis for: 7_ Calculated: C, 39.29; H, 4.03; N, 10.18 Found: C, 39.71; H, 3.91; N, 10.27 Intermediate 2a 2- (2-B-cinylamino-ethoxy) -6-nor ro-phenylamine A mixture of 2- (2-chloro-ethoxy) -6-nitro-phenylamine (3.0 g, 13.8 mmol) and benzylane (9.0 g, 84. 0 mmole) was heated 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 / cm2 (0.1 mm of mercury) .The residue was poured into 1 N sodium hydroxide (300 ml) and extracted with ethyl acetate (2X, 300 mi). 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 oil. Purification by chromatography (500 g of silica gel, ethyl acetate: 2 M NH 3 in methanol, 20: 1) gave 3.54 g (89.3%) of a red semi-solid, m.p. 33-60 ° C; MS The m / e 287 (M +). Elemental analysis for C? 5 H 17 N 3?: Calculated: C, 62.71; H, 5.96; N, 14.62 Found: C, 62.64; H, 6.04; N, 14.23 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 benzylamine, 4-methyl-benzylamine, 1-naphthalene-methylamine, 4-tert-butyl-benzylamine, thiophen-2-methyl-amine, 4-chloro-benzylamine, thiophene-3 -methylamine, or 1,2,3,4-tetrahydroisoquinolin were obtained: 2b 2- [2- (4-Methyl-benzylamino) -ethoxy] -6-nitrophenylamine as a yellow solid (89%), mp 55-57 ° C; The m / e 301 (M +). Elemental analysis for C16H19N.O3: 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-ni ro-phenylamine as a viscous orange oil (85.5%); MS The m / e 301 (M +).

Elemental analysis for C1SH19N3O3: Calculated: C, 63.77; H, 6.36; M, 13.94 Found: C, 63.66; H, 6.28; N, 13.89 2d 2-. { 2- [(Naphthalen-1-ylmethyl) -amino] -ethoxy} -6-ni tro-phenylamine as a yellow solid (76.3%); p.f. 66-67 ° C; MS The m / e 337 (M +). Elemental analysis for C19H19N3O3: 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-nitro-phenylamine as a viscous orange oil (83.3%); MS The m / e 343 (M +) which was analyzed as a quarter of the hydrate. 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- [2- (4-Chloro-benzylamino) -ethoxy] -6-ni-tro-phenylamine as an orange solid (87.8%), m.p. 61.62 ° C; EM The m / e 322/324 (M +) which was analyzed as the fourth part_ of the h.idrate. Elemental analysis for C? 5Hla] r? * 0.25 H20: Calculated: C, 55.22; H, 5.10; N, 12.88 Found: C, 55.27; H, 4.96; N, 12.88 2g 2- (2-Benzylamino-ethoxy) -4-chloro-6-ni ro-phenylamine as an orange-brown colored solid (54.0%), m.p. 87-88 ° C; EM The m / e 321/323 (M +). Elemental analysis for Ci5H? 6ClN3? 3: Calculated: C, 55.99; H, 5.01; N, 13.06 Found: C, 55.85; H, 4.90; N, 13.13 2h_ 4-Chloro-2-nitro-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 Ci3H? 4ClN302S: Calculated: C, 47.67; H, 4.33; N, 12.75 - Found: C, 47.54; H, 4.11; N, 13.06 2i 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 C13H14CIN3-O2S: Calculated: C, 47.67; H, 4.33; N, 12.75 Found: C, 47.54; H, 4.18; N, 12.80 2j 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 +). Elemental analysis for C 17 H 19 N 3 O 2: Calculated: C, 65.16; H, 6.11; N, 13.41 Found: C, 64.87; H, 6.11; N, 13.40 Intermediate 3a N- [2- (2-Amino-3-nitro-phenoxy) -tyl] -N-benzyl-2, 2,2-trifluoroacetamide To a solution of 2- (2-benzylamino-ethoxy) -6 -nitro-phenylamine (2a, 0.5 g, 1.74 mmoles) and triethylamine (0.32 ml, 3.48 mmol) in anhydrous methylene chloride (10 ml) at 23 ° C was added trifluoroacetic anhydride (0.32 ml, 2.26 mmol). 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 Ci7H1 £ F3N304: 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- (-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- [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: 3b N- [2- (2-Amino-3-ni ro-phenoxy) -ethyl] -2,2,2-trifluoro-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? 8H? 8F3-Nr3? 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-ni tro-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 C18H18F 3O4: 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-nor ro-f enoxy) -ethyl] -2,2,2-tri luoro-N-na talen-1-ylmethyl-acetamide as a yellowish colored solid -naranj a (75.3%), pf 133-135 ° C; MS M / e 433 (M +). Elemental analysis for C 21 H 18 F 3 N 3 O 4: 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-ni tro-f enoxy) -e il] -N- (4-tert-butyl-benzyl) -2, 2, 2-trifluoroacetamide as a yellow solid (82.0%), pf 80-82 ° C; MS The m / e ~ 439 (M +). Elemental analysis for C21H24F3N3O4: 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-ni ro-f-enoxy) -ethyl] -N- (4-chloro-benzyl) -2,2-trifluoro-acetamide as a yellow solid (84.0%) ), pf 138-139 ° C; MS (+) BAR m / e 418/420 (M + H +). Elemental analysis for C17H15CIF3N3O4: Calculated: C, 48.88; H, 3.62; N, 10.06 Found: C, 48.66; H, 3.47; N, 9.82 3g N- [2- (2-Amino-5-chloro-3-ni ro-f-enoxy) -ethyl] -N-benzyl-2,2,2-trifluoroacetamide as a yellow solid (67.9%), pf 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 3h N- [2- (2-amino-5-chloro-3-ni tro-enoxy) -ethyl] -2,2,2-tri luoro-N-thiophen-2-ylmethyl-acetamide as a yellow solid (59.6 %), pf 97-98 ° C; EM The m / e 423/425 (M +). Elemental analysis for C? 5H13ClF3N? S: Calculated: C, 42.51; H, 3.09; N, 9.92 Found: C, 42.37; H, 2.97; N, 9.84 3i N- [2- (2-Amino-5-chloro-3-nitro-enoxy) -ethyl] -2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide as a yellow solid (80.0%) ), pf 149-150 ° C; EM The m / e 423/425 (M +). Elemental analysis for C 15 H 3 ClF 3 N 3 O 4 S: Calculated: C, 42.51; H, 3.09; N, 9.92 Found: C, 42.02; H, 2.95; N, 9.78 Intermediate 4a N-Bensyl-N- [2- (2, 3-diamino-phenoxy) -ethyl] -2,2,2-trifluoroacetamide To a mixture of N- [2- (2-amino-3-nitro -phenoxy) -ethyl] -N-benzyl-2,2,2-trifluoroacetamide (3a, 2. 4 g, 6.26 mmoles) 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; MS (+) BAR m / e 354 (M + H +). Elemental analysis for Ci7H? 8F3lr? 2: Calculated: C, 56.58; H, 4.72; N, 12.38 Found: C, 57.49; H, 5.10; N, 11.86 Using this general procedure N- [2- (2-amino-3-nitro-phenoxy) -ethyl] -2,2-trifluoro-N- (4-methyl-benzyl) acetamide, N- [3 -. { 2-amino-3-ni tro-phenoxy) -propyl] -N-benzyl-2,2,2-trifluoroacetamide, N- [2- (2-amino-3-nitro-phenoxy) -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-nitro-phenoxy) -ethyl] -2, 2, 2, -tri-fluoro-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) -et -yl] -N-benzyl-2,2,2-trifluoro-acetamide, N- [2- (2-amino-5-chloro-3-nitro-phenoxy) -ethyl] -2,2, 2-trifluoro-N-thiophen-2-ylmethyl-acetamide and N- [2- (2-amino-5-chloro-3-nitro-phenoxy) -ethyl] -2,2, 2, ~ trifluoro-N-thiophen-3-ylmethyl-1-acetamide gave: 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 18 H 20 FN 3 O 2: Calculated: C, 58.85; H, 5.49; N, 11.44 Found: C, 59.00; H, 5.42; N, 11.48 4d N- [2- (2, 3-Diamino-phenoxy) -ethyl] -2,2, 2-trifluoro-N-naph alen-1-ylmethyl-acetamide as a viscous yellow oil (63.0%); MS (+) BAR m / e 404 (M + H +). Elemental analysis for C21H20F3N3O2: 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-diamino-phenoxy) -ethyl] -2,2,2-trifluoroacetamide as a viscous brown oil (72.7%); MS The m / e 409 (M +). 4f J-j4-Chloro-benzyl) -N- [2- (2, 3-diamino-phenoxy) -ethyl] -2, 2, 2-trifluoroacetamide as a brown oil (80.9%), MS m / e 387/389 (M +). Elemental analysis for C17H17CIF3N3O2 V Calculated: C, 52.65; H, 4.42; N, 10.84 Found: C, 52.47; H, 4.51; N, 10.60 4g N-Benzyl-N- [2- (2, 3-diamino-5-chloro-phenoxy) -ethyl] -2,2,2-trifluoroacetamide as a viscous brown oil (76.2%); EM The m / e 387/389 (M +). Elemental analysis for C17H17CIF3N3O2: Calculated: C, 52.65; H, 4.42; N, 10.84 Found: C, 52.47; H, 4.39; N, 10.90 4h N- [2- (2, 3-Diamino-5-chloro-phenoxy) -ethyl] -2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide as a viscous brown oil (71.4%); EM The m / e 393/395 (M +). Anál i s i l emental for C15H3.5CI F3N3O2S: Calculated: C, 45.75; H, 3.84; N, 10.67 Found: C, 45.58; H, 3.93; N, 10.64 4i N- [2- (2, 3-Di mino-5-chloro-phenoxy) -ethyl] -2,2,2-trx luoro-N-txof en-3-ylmethyl-acetamixed as a viscous brown oil (75.0 %); EM The m / e 393/395 (M +). Elemental Analysis for C15H15CIF3N O2S: Calculated: C, 45.75; H, 3.84; N, 10.67 Found: C, 45.39; H, 3.84; N, 10.56 Intermediate 5a N-Benzyl-2, 2, 2- ri luoro-N- [2- (2-oxo-2, 3-di xdro-lH-benzoimidazol-4-yloxy) -ethyl-acetamide A mixture of N-benzyl-N - [2- (2, 3-diamino-phenoxy) -ethyl] -2,2,2-trifluoroacetamide (0.57 g, 1.61 mmol) and 1,1 '-thiocarbonyldiimidazole (0.49 g, 3.05 mmol) in anhydrous tetrahydrofuran (30 mi) 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) afforded 0.54 g (85.2%) of a yellowish colored solid. Crystallization from ethyl acetate-hexane gave a white solid, m.p. 158-160 ° C; MS (+) BAR m / e 395 (M + E *). Elemental analysis for C? 8HlsF3N3? 3: Calculated: C, 54.52; H, 3.74; N, 10.56 Found: C, 54.68; H, 4.08; N, 10.63 Using this general procedure N- [2- (2, 3-diamino-phenoxy) -ethyl] -2, 2, 2-trifluoro-N- (4-methyl-benzyl) -acetamide, N-benzyl-N - [3- (2, 3-diamino-phenoxy) -propyl] -2, 2, 2-trifluoro-acetamide, N- [2- (2, 3-diamino-phenoxy) -ethyl] -2, 2, 2-trifluoro-N-naphthalene-l-ylmethyl-acetamide, N- (4-tert-butyl-benzyl-N- [2- (2, 3-diamino-phenoxy) -ethyl] -2, 2, 2-trifluoro -acetamide, N- (4-chloro-benzyl) -N- [2- (2, 3-diamino-phenoxy) -ethyl] -2,2, 2-trifluoroacetamide, N-benzyl-N- [2- (2, 3-diamino-5-chloro-phenoxy) -ethyl] -2, 2, 2-trifluoroacetamide, N- [2- (2, 3-diamino-5-chloro-phenoxy) -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 provided: "~ 5b 2, 2, 2 -Trxf luoro-N- (4-methyl-bensyl) -N- [2- (2-thioxo-2,3-dihxdro-lH-benzoimidazol-4-yloxy) -e]] -acetamide as a white solid (90.9%), mp 195-196 ° C; MS The m / e 409 (M +). Elemental Analysis for CigHiaFaNaO O ^ Si Calculated: C, 55.47; H, 4.43; N, 10.26 Found: C, 55.40; H, 4.24; N, 10.05 5c N-Benzyl-2, 2, 2-trif luoro-N- [3- (2-thioxo-2,3-dihydro-lH-benz or imidazol-4-oxoxy) -propyl] -acetamide as a foam yellow (99.0%); MS The m / e 409 (M + H +), which was analyzed for a third-fourth part of hydrate. Elemental analysis for C? 9H? 8F3N3? 3? S «0.75 H20: Calculated: C, 53.96; H, 4.65; N, 10.40 Found: C, 54.05; H, 4.49; N, 10.09 5d 2,2, 2-Trifluoro-N-naph talen-1-ylmethyl-N- [2- (2-thioxo-2,3-dihydro-lH-benzimidazol-4-yloxy) -ethyl-acetamide as a white solid (95.0 %), mp 102-103 ° C; MS The m / e 445 (M +). Elemental Analysis for C22H18F N3O3S: Calculated: C, 58.73; H, 4.14; N, 9.34 Found: C, 58.84; H, 4.02; N, 9.17 5e N- (4-tert-Butyl-benzyl) -2,2, 2-trifluoro-N- [2- (2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] - asetamide as a white solid (86.4%), mp 199-200 ° C; MS M / e 451 (M +). Elemental analysis for C22H24F N3O2S: Calculated: C, 58.52; H, 5.36; N, 9.31 Found: C, 58.46; H, 5.36; N, 9.25 5f N- (4-Chloro-benzyl) -2,2, 2-trifluoro-N- [2- (2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -acetamide as a solid white (72.0%), mp 194-196 ° C; EM The m / e 429/431 (M +). Elemental analysis for C18H15CIF3 3O3S: Calculated: C, 50.30; H, 3.52; N, 9.78 Found: C, 50.50; H, 3.54; N, 9.51 5g N-Benzyl-N- [2- (6-chloro-2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -i] -2,2,2-trifluoroacetamide as a solid white (93.8%), mp 201-202 ° C. Elemental Analysis for C18H15CIF3N3O2S: Calculated: C, 50.30; H, 3.52; N, 9.78 Found: C, 50.00; H, 3.40; N, 9.67 5h N- [2- (6-chloro-2-thioxo-2/3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -2,2, 2-trif luoro-N-txof en-2-ylmethyl -acetamide as a white solid (68.2%), mp 183-1854 ° C; EM The m / e 435/437 (M +). Elemental analysis for C? 6Hi ClF3N? Sa: Calculated: C, 44.09; H, 3.01; N, 9.64 Found: C, 43.76; H, 2.7 N, 9.53 5i N- [2- (6-Chloro-2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -2,2,2-trifluoro-N-thio en-3-ylmethyl- acetamide as a white solid (64.9%), mp 179-180 ° C; EM The m / e 435/437 (M +). Elemental analysis for deH ^ ClFs ^ OsS: Calculated: C, 44.09; H, 3.01; N, 9.64 Found: C, 44.11; H, 2.80; N, 9.47 Intermediate 6 3- [2- (3,4-Dihydro-lH-isoquinolxn-2-xl) -ethoxy] -benzene-1,2-diamine The general procedure used in intermediate 4 using 2- [2- (3, 4-dihydro-lH-isoquinolin-2-yl) -ethoxy] -6-nitro-f-enylamine (2 j) yielded 3- [2- (3,4-dihydro-lH-isoquinolin-2-yl) -ethoxy] -benzene-1, 2-diamine as a solid (95%), mp 76-77 ° C. This material was characterized as the dihydrochloride salt 0.4 H20; MS The m / e 283 (M +). Elemental analysis for C? 7H2? N30 * 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 7 4-Chloro-2- (2-chloro-ethoxy) -6-nor ro-phenylamine A solution of 2- (2-chloro-ethoxy) -6-nitro-phenylamine (la, 30.0 g, 0.14 moles), N-chlorosuccinamide and acetonitrile (1.3 1) was heated to 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 C 8 H 8 Cl 2 N 2 O 3: 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-benzoimidazole-2-thione A suspension of potassium carbonate (0.90 g, 6.50 mmol) and N-benzyl-2,2,2-trifluoro-N - [2- (2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -acetamide (0.367 g, 0.928 mmol) in methanol-water (30 mL: 2 mL) was heated to reflux for 2 hours, and 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 crude base. Purification through chromatography (70 g of silica gel, ethyl acetate: 2N NH 3 in methanol, 20: 1) provided 0.27 g (9T.2%) ~ of a white solid. Crystallization of methanol gave white needles, m.p. 147-149 ° C; MS m / e BAR 300 (M + H +) containing methanol. Elemental analysis for C? 6H? 7 N3OS * 0.75 CH40 Calculated: C, 62.20; H, 6.23; N, 12.99 Found: C, 62.10; H, 6.07; N, 13.26 To a solution of 4- (2-benzylamino-ethoxy) -1,3-dihydro-benzoimidazole-2-thione (0.195 g, 0.65 mmol) in methanol (40 mL) was added an excess of 1N hydrogen chloride in ether to yield 0.155 g (67.4%) of the monohydrated hydrochloride salt of the title compound as a white solid, mp 253-255 ° C; MS m / e (+) BAR 300 (M + H +). Elemental analysis for C? 6HnN3OS »HCl • H20: Calculated: C, 54.31; H, 5.70; N, 11.87 Found: C, 54.62; H, 5.48; N, 12.00 Example 2 4 - [2- (4-Methyl-benzylamino) -ethoxy] -1,3-dihydrobenzoimidazole-2-thione Following the general procedure used in Example 1, and using 2, 2, 2-trifluoro-N - (4-ethyl-benzyl) -N- [2- (2-thioxo-2,3-dihydro-lH-benzimidazol-4-yloxy) -ethyl] -acetamide (5b) was given: 4- [2- ( Methyl-benzylamino) -ethoxy)] -1,3-dihydro-benzoimidazole-2-thione as a quarter of hydrate in white solid (97.2%) mp 154-156 ° C; MS m / e 313 (M +). Elemental analysis for Ci7H19N? S »0.25 H20: Calculated: C, 64.23; H, 6.18; N, 13.22 Found: C, 64.37; H, 5.93; N, 13.07 Addition of excess 1N hydrogen chloride in ether gave 4- [2- (4-methyl-benzylamino) -ethoxy] -1,3-dihydro-benzoimidazole-2-thione • HCl • hydrate as a white solid (71.1%), pf > 250 ° C; MS m / e (+) BAR 314 (M + H) +. Elemental analysis for C-17Hi9N30S »HCl» H20 Calculated: C, 55.50; H, 6.03; N, 11.42 Found: C, 55.81; H, 5.79; N, 11.33 Example 3 4 - (2-benzylamino-propoxy) -1, 3-dihydro-benzoimidazole-2-thione The general procedure used in Example 1 and using N-benzyl-2,2,2-trifluoro-N - [3- (2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -propyl-acetamide (5c) gave: 4- (2-benzylamino-propoxy) -1,3-dihydro-benzoimidazole- 2-thione as a white solid (64.4%), mp 203-204 ° C; MS m / e 313 (M +). Elemental analysis for Ci7H? 9 3OS * 0.25 H20: Calculated: C, 64.23; H, 6.18; N, 13.22 Found: C, 64.10; H, 5.08; N, 12.84 The addition of excess 1 N hydrogen chloride in ether gave a quarter of hydrate in hydrochloride salt of 4- (2-benzylamino-propoxy) -1,3-dihydro-benzoimidazole-2-thione as a white solid (92.5%), pf 243-244 ° C; EM m / e 313 (M) +. Elemental analysis for Ci7H19N3OS * HCl * 0.25H20 Calculated: C, 57.62; H, 5.83; N, 11.86 Found: C, 57.58; H, 5.71; N, 11.72 Example 4 4 -. { 2 - [(Na talen-1-ylmethyl) -amino] -ethoxy} -1, 3-dihyd o-benzoimidazole-2-thione The general procedure used in Example 1 and using 2, 2, 2-tri-fluoro-N-naphthalen-1-ylmethyl-N- [2- (2-thioxo-2 , 3-dihydro-l-benzoimidazol-4-yloxy) -ethyl] -acetamide (5d) provided: 4-. { 2- [(Naphthalen-1-ylmethyl) -amino] -ethoxy} -1,3-dihydro-benzoimidazole-2-thione • 0.5 ethyl acetate as a white solid (66.6%), m.p. 191-193 ° C; MS m / e The 349 (M +). Elemental analysis for C2oH? 9 3? S «0.5 C4H802: Calculated: C, 67.15; H; 5.89; N, 10.68 Found: C, 66.97; H, 5.75; N, 10.76 The addition of excess 1N hydrogen chloride in ether to the above product gave three quarters of hydrated hydrochloride salt of the title compound as a white solid (90.0%), m.p. 240-242 ° C; EM m / e The 349 (M) +. Elemental analysis for C2oHi9N3? S »HCl» 0.75_H20 Calculated: C, 60.14; H; 5.43; N, 10.52 Found: C, 60.42; H, 5.48; N, 10.09 Example 5 4- [2- (4-tert-Butyl-benzylamino) -ethoxy] -1,3-dihydrobenzoimidazole-2-thione The general procedure used in Example 1 and using N- (4- tert-butyl- benzyl) -2, 2, 2-trifluoro-N- [2- (2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -acetamide (5e) provided: 4- [2- (4- tert -Butyl-benzylamino) -ethoxy] -l, 3-dihydro-benzoimidazole-2-thione as a white solid (79.3%), mp. 125-127 ° C; MS m / e 355 (M +). Elemental Analysis for C20H25 3OS: Calculated: C, 67.57; H, 7.09; N, 11.82 Found: C, 67.02; H, 7.00; N, 11.67 Treatment of the above free base with excess 1N hydrogen chloride in ether gave a quarter of the hydrate of the hydrochloride salt of the title compound as a white solid (90.0%), m.p. > 250 ° C; EM m / e 355. (M) +. Elemental analysis for C2oH25N3OS »HC1« 0.25 H20: Calculated: C, 60.59; H, 6.74; N, 10.60 Found: C, 60.50; H, 5.68; N, 10.44 Example 6 4- [2- (Chloro-benzylamino) -ethoxy] -1,3-dihydrobenzoimidazole-2-thione The general procedure used in Example 1 and using N- (4-Chloro-benzyl) -2, 2, 2-trifluoro-N- [2- (2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -acetamide (5f) gave: 4- [2- (4-Chloro- benzylamino) -ethoxy] -l, 3-dihydro-benzoimidazole-2-thione as a white solid (85.9%), mp 160-162 ° C; MS m / e (+) BAR 334/336 (M + H +). Elemental analysis for Ci6H? EClN30S: Calculated: C, 57.57; H, 4.83; N; 12.59 Found: C, 57.17; H, 4.64; N, 12.35 Treatment with excess N hydrogen chloride in ether gave the hydrochloride salt of the title compound as a white solid (90.0%), m.p. 204-205 ° C; EM m / e 333/335 (M) +. Elemental analysis for Ci6H16N 0S * HCl: Calculated: C, 51.90; H, 4.63; N, 11.35 Found: C, 51.86; H, 4.46; N, 11.22 Example 7 4- (2-Benzylamino-ethoxy) -6-chloro-l, 3-dihydrobenzoimidazole-2-thione The general procedure used in Example 1 and using N-benzyl-N- [2- (6-chloro -2-thioxo-2, 3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -2,2,2-trifluoroacetamide (5g) provided: 4- (2-benzylamino-ethoxy) -6-chloro -l, 3-dihydro-benzoimidazole-2-thione as a white solid (88.2%), mp. 234-237 ° C; MS m / e 333/335 (M +).

Elemental analysis for C? 6H? 6ClNaOS * 0.4 H20: Calculated: C, 56.35; H, 4.97; N, 12.32 Found: C, 56.43; H, 4.76; N, 12726 Reaction of the above compound prepared with excess of 1N hydrogen chloride in ether gave 4- (2-Benzylamino-ethoxy) -6-chloro-1,3-dihydro-benzomidazole-2-thione * HCl as a solid white (95.0%), mp > 250 ° C; MS m / e 333/335 (M +). Elemental Analysis for Ci6H? 6Cl 30S * HCl: Calculated: C, 51.90; H, 4.63; N, 11.35 Found: C, 51.79; H, 4.62; N, 11.20 Example 8 6-Chloro-4-. { 2- [(thiophen-2-ylmethyl) -amino] -ethoxy} -1, 3-dihydro-benzoimidazole-2-thione The general procedure used in Example 1 and using N- [2- (6-chloro-2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -2, 2, 2-trifluoro-N-thiophen-2-ylmethyl-acetamide (5h) provided: 6-Chloro-4-. { 2- [(thiophen-2-ylmethyl) -amino] -ethoxy} -l, 3-dihydro-benzoimidazole-2-thione * hemihydrate as a white solid (92.0%), m.p. 183-184 ° C; MS m / e 339/341 (M +). Elemental analysis for Ci H14ClN3? S3 »0.5 H20: Calculated: C, 48.20; H, 4.33; N, 12.04 Found: C, 48.30; H, 3.99; N, 11.91 The hydrochloride salt of the title compound was prepared as a white solid (90.0%), m.p. > 250 ° C; MS m / e (+) BAR 340 (M + H) + Elemental analysis for C14H14CIN3OS3.HCl: Calculated: C, 44.68; H, 4.02; N, 11.17 Found: C, 44.28; H, 3.87; N, 10.83 Example 9 6-Chloro-4-. { 2- [(io en-3-ylme il) -amino] -ethoxy} -1, 3-dihydro-benzoimidazole-2-thione The general procedure used in Example 1 and using N- [2- (6-chloro-2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] -2, 2, 2-trifluoro-N-thiophen-3-ylmethyl-acetamide (5i) provided: 6-Chloro-4-. { 2- [(t-pheno-3-ylmethyl) amino] -ethoxy} -1,3-dihydro-benzoimidazole-2-thione as a white solid (77.0%), m.p. 197-198 ° C; MS m / e (+) BAR 340/342 (M + H) + Elemental analysis for C 14 H 14 CIN 3 O 3: Calculated: C, 49.48; H, 4.15; N; 12.36 Found: C, 49.27; H, 4.14; N, 12.30 The hydrochloride salt of the title compound was prepared as a white solid (90.0%), m.p. > 250 ° C; MS m / e (+) BAR 340 (M + H) +. Elemental analysis for C14H14CIN3OS3 * HC1: Calculated: C, 44.68; H, 4.02; N; 11.17 Found: C, 44.28; H, 3.87; N, 10.83 Example 10 4- [2- (3,4-Dihydro-lH-isoquinolin-2-yl) -ethoxy] -1,3-dihydro-benzoimidazole-2-thione Following the general procedure used in Example 1 and using 2- [2- (3,4-dihydro-lH-isoquinolin-2-yl) -ethoxy] -6-nitrophenylamine (2j) gave the title compound as a yellow solid (60.0%), mp. 249-250 ° C; MS m / e 325 (M +). Elemental analysis for C? 8Hi9 3OS: Calculated: C, 66.43; H, 5.88; N, 12.91 Found: C, 66.07; H, 5.92; N, 12.85 The hydrochloride salt of the title compound was prepared as a light yellow solid (90.0%), m.p. 213-214 ° C; MS m / e 325 (M) +. Elemental analysis for C? 6H? 6Cl 3? S "HCl: Calculated: C, 59.74; H, 5.57; N, 11.61 Found: C, 59.12; H, 5.52; N, 11.50.

PHARMACOLOGY The compounds of this invention are dopamine autoreceptor agonists, that is, they serve to modulate the synthesis and release of the neurotransmitter of dopamine. They are thus useful for the treatment of disorders of the dopaminergic system, such as schizophrenia, Parkinson's disease and Tuorette syndrome. Such agents are partial agonists in the post-synaptic dopamine D2 receptor and are thus useful in the treatment of alcohol and drug addiction. The affinity for the dopamine autoreceptor was established by a modification of the standard experimental test procedure of See in and Schaus, European Journal of Pharmacology 203: 105-109, 1991, wherein homogenized rat brain striated tissue was incubated with 3 H-quinpirole (Quin.) And various concentrations of the test compound, filtered, 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) wherein homogenized limbic brain tissue was incubated with 3 H-spiroperidol (Spiper.) And various concentrations of the test compounds, filtered, washed and shaken with a Hydrofluor scintillation cocktail (National Diagnostics) and it was counted in a Packard 460 CD scintillation counter. The results of the tests with representative compounds of this invention are given in the following table.

Hence, the compounds of this invention effect the synthesis of a dopamine neurotransmitter and thus are used in the treatment of dopaminergic disorders such as schizophrenia, Parkinson's disease, Tourette's syndrome, addition to alcohol, addition to cocaine and addition to the analogous drugs Applicable solid carriers for the pharmaceutical compositions containing the compounds of this invention may include one or more or substances which may also act as flavoring agents, lubricants, solubilizers, 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 to prepare 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 J or pharmaceutically acceptable oils or fats. The liquid carrier may 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 those containing additives such as those above, for example, cellulose derivatives, preferably a solution of sodium carboxymethylcellulose) alcohols (including monohydric alcohols and polyhydric alcohols, for example, glycols), and their derivatives and oils (e.g. 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. Sterile solutions can also be administered intravenously. Oral administration can be either a liquid dosage form or a solid dosage form. Preferably, the pharmaceutical composition is in unit dosage form, for example, tablets or capsules. In such form, the composition is sub-divided into unit doses containing appropriate amounts of the active ingredient; the unit dosage form can be packaged compositions, for example, powders in sachets, flasks, ampoules, pre-filled syringes or sachets containing liquids. The unit dosage form can be for example, a capsule or tablet itself, or it can be the appropriate number of such compositions in packaged form. The dosage that is to be used in the treatment of a specific psychosis must be determined subjectively by the attending physician. The variables involved include the specific psychosis and the patient's size, age and response pattern.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (19)

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

1. A compound of the formula: H I characterized in that: R: is hydrogen or alkyl of 1 to 6 carbon atoms; R 'is hydrogen or alkyl of 1 to 6 carbon atoms; R- is selected from hydrogen, or a straight and branched chain alkyl group having up to 10 carbon atoms, cyclohexylmethyl or -CH¿) nAr, wherein Ar is phenyl, naphthyl, thienyl, furanyl or pyridyl, each optionally substituted by one or two substituents independently selected from alkyl of 1 to 6 carbon atoms, halogen, alkoxy of 1 to 6 carbon atoms and trifluoromethyl; 23 or NR R is 1, 2, 3, 4-tetrahydroquinolin-1-yl or 1, 2, 3, -tetrahydroisoquinolin-2-yl; m is 1 - 5; n is 1 or 2; 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 R1 or R ~ is benzyl, substituted benzyl, thienylmethyl, furanyl, tyl, phenylbutyl, cyclohexylmethyl or 4-fluorobutyrophenone.

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

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

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

6. A compound according to claim 1, characterized in that it is 4-. { 2- [(naphthal en-1-lmethyl) -amino] -ethoxy} -! 3 -di-idro-benzoimidazol-2-thione 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-benzoimidazole-2-thione or a pharmaceutically acceptable salt thereof.

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

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

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

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

12. A compound according to claim 1, characterized in that it is 4- [2- (3, -dihydro-lH-isoquinolin-2-yl) -ethoxy} -! 3-dihydro-benzoimidazole-2-thione or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 1, characterized in that it is a pharmaceutically acceptable salt thereof.

14. Use of a compound of the formula. I R 'is hydrogen or alkyl of 1 to 6 carbon atoms; R is hydrogen or alkyl of 1 to b carbon atoms; R3 is selected from hydrogen, or a straight and branched chain alkyl group having up to 10 carbon atoms, cyclohexylmethyl or -CH2) mAr, wherein Ar is phenyl, naphthyl, thienyl, furanyl or pyridyl, each optionally substituted by one or two substituents independently selected from alkyl of 1 to 6 carbon atoms, halogen, alkoxy of 1 to 6 carbon atoms and trifluoromethyl; or NR2R3 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; Y is halogen, alkyl of 1 to 6 carbon atoms .. and alkoxy of 1 to 6 carbon atoms; and pharmaceutically acceptable salts thereof for the preparation of a medicament for treating diseases in a mammal that reacts to treatment with a D2 dopamine antagonist.

15. The use according to claim 14, characterized in that the disease treated is schizophrenia.

16. The use according to claim 14, characterized in that the disease treated is Tourette's syndrome.

17. The use according to claim 14, characterized in that the disease treated is Parkinson's disease.

18. The use according to claim 4, characterized in that the disease treated is addiction to the drug or alcohol.

19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the formula characterized * because: R1 is hydrogen or alkyl of 1 to 6 carbon atoms; R * is hydrogen or alkyl of 1 to 6 carbon atoms; R 'is selected from hydrogen, or a straight and branched chain alkyl group having up to 10 carbon atoms, cyclohexylmethyl or -CH) mAr, wherein Ar is phenyl, naphthyl, thienyl, furanyl or pyridyl, each optionally substituted by one or two of its substituents independently selected from alkyl of 1 to 6 carbon atoms, halogen, alkoxy of 1 to 6 carbon atoms and trifluoromethyl; or NR'R 'is 1, 2, 3, 4-1-tetrahydroquinolin-1-yl or 1,2,3,4-tetrahydroisoquinolin-2-yl;. m is 1- 5; n is l or 2; Y is halogen, alkyl of 1 to 6 carbon atoms, and alkoxy of 1 to 6 carbon atoms; and the pharmaceutically acceptable salts thereof.