JP2001509814A - 4-Aminoalkoxy-1H-benzimidazole derivatives, their preparation and their use as dopamine autoreceptor (D lower 2) agonists - Google Patents

Abstract

(57) The present invention provides a compound of the formula (I): Wherein R ¹ is hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, a linear or branched alkyl group having up to 6 carbon atoms, or, if desired, halogen, amino, nitro, hydroxy, C, ₁ -C ₆ benzyl which may be substituted with 1-3 substituents selected from alkoxy; R ² is hydrogen or C ₁ -C ₆ alkyl; R ³ is hydrogen, straight up to 10 carbon atoms A chain or branched chain alkyl group, cyclohexylmethyl or — (CH ₂ ) _m Ar, where Ar is phenyl, thienyl, furanyl or pyridinyl, each optionally being halogen, C ₁ -C ₆ alkoxy, NR ² R ³ may be substituted with one or two substituents selected from trifluoromethyl or C ₁ -C ₆ alkyl); alternatively, NR ² R ³ is 1,2,3,4-tetrahydroquinolyl 1-yl or 1,2,3,4-tetrahydroisoquinolin-2-yl; Y = halogen, lower alkyl, amino, and lower alkoxy; n = 1 to 5], or a pharmaceutically acceptable salt thereof. about D ₂ dopaminergic compound is a salt. These D ₂ dopaminergic compound, schizophrenia, Parkinson's disease and is useful in the treatment of Tourette's syndrome, and drug addiction or alcohol addiction.

Description

DETAILED DESCRIPTION OF THE INVENTION           4-aminoalkoxy-1H-benzimidazole derivatives,   Their preparation and their dopamine autoreceptors (D_Two) Use as agonist                                 Field of the invention   The present invention relates to dopamine D_TwoHas agonist activity and therefore schizophrenia, Parkin Useful for treating Song disease, Tourette syndrome, and drug or alcohol addiction 4- (aminoalkoxy) -1H-benzimidazole.                                 Background of the Invention   Successful attempts to induce antipsychotic activity using dopamine autoreceptor agonists (Dorsini et al., Advances in Biochemical Psychopher Macology (Adv. Biochem. Psychopharmacol.), 16, 645-648, 1977; Taminga (Tam- Minga) et al., Science, 200, 567-568, 1975; and Tamminga. Et al., Psychiatry, 398-402, 1986). Recently, dopamine D_TwoTo the receptor A method for measuring intrinsic activity in mice was reported (Lahti et al., Molecular Pharmacology (Mol. Pharm.), 42, 432-438, 1993). The intrinsic activity of this receptor "Low affinity agonist" (low Ag) state and "high affinity agonist" (high Ag) of this receptor Expected with state ratio, low Ag / high Ag. These ratios are Correlates with the agonistic, partial agonistic and antagonistic activities of the compounds obtained. Such activity characterizes the compound's ability to induce an antipsychotic effect.   According to the present invention, there is provided a group of compounds which are useful antipsychotics. The present invention Are dopamine agonists with various intrinsic activities, some of which Is a selective autoreceptor agonist and therefore a partial agonist (i.e. Post-synaptic dopamine D_TwoActivates only autoreceptors for the receptor). did Therefore, they have been found to be clinically effective in the treatment of schizophrenia. Have been identified as the cause of serious side effects often exhibited by certain drugs. Functional modulation of the brain dopamine system without excessive blockade of post-naptic dopamine receptors Give a clause. Activation of dopamine autoreceptors is an inhibition of dopamine synthesis and release But also a decrease in neuronal excitation, and therefore hyperactivity of the dopamine system Means to control the The compounds of the present invention have also been found to have high intrinsic activity. And therefore they are available as natural neurotransmitters, It can function as an agonist. Therefore, they differ in dopamine concentration. It is useful in the treatment of common diseases, and probably in the treatment of Parkinson's disease. Could be used as a substitute. The compounds of the invention are essentially pyramidal Has no external roadside effects (EPS).                               Description of the prior art   Numerous compounds structurally related to the compounds of the present invention have been claimed in the prior art. I have.   JP 02306916A has the following formula: [Where X is S or N] Benzoazole compounds are claimed. These are Atheros Atherosclerosis, ischemic heart disease, chronic arterial occlusion, and acute or chronic nephritis Is a platelet adhesion inhibitor for the treatment of In the above formula, R₁As-(OA )_m-NR^FourR^Five(Where A is lower alkylene, m is 0 or 1, R^FourAnd R^FiveIs , Hydrogen, phenyl (lower) alkyl, etc., or NR^FourR^FiveIs 5-6 members A saturated or unsaturated heterocyclic ring)._TwoAs desired, c Lower alkoxy, lower alkyl, hydroxy, halogenated Even if substituted with 1 to 3 substituents selected from Good phenyl and the like.   DE 3830060 includes the following formula useful for treating cardiovascular disorders and stroke: [Wherein, R^FourIs methyl, cyano, carboxamide or aminomethyl; R^FiveIs H Or alkyl; R⁶Is alkyl or cycloalkyl;^FiveAnd R⁶ Forms a cyclohexane ring] Claims 2-arylbenzimidazole hemagglutination inhibiting compounds represented by are doing.                               Summary of the Invention   The compounds of the present invention have the following formula I: [Where,   R¹Is hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoro Propyl, a straight or branched chain alkyl group having up to 6 carbon atoms, or, if desired, Halogen, amino, nitro, hydroxy, C₁-C₆1 selected from alkoxy Benzyl optionally substituted with up to 3 substituents;   R^TwoIs hydrogen or C₁-C₆Alkyl;   R^ThreeIs hydrogen, a linear or branched alkyl group having up to 10 carbon atoms, cyclohexyl Methyl or-(CH_Two)_mAr (where Ar is phenyl, thienyl, furanyl Or pyridinyl, each optionally being halogen, C₁-C₆Alkoxy , Trifluoromethyl or C₁-C₆1 to 2 substituents selected from alkyl May be substituted); or   NR^TwoR^ThreeIs 1,2,3,4-tetrahydroquinolin-1-yl or 1,2,3,4- Tetrahydroisoquinolin-2-yl;   Y = halogen, lower alkyl, amino, and lower alkoxy;   n = 1-5] And a pharmaceutically acceptable salt thereof.   Pharmaceutically acceptable acid addition salts having the utility of a free base are known from the art. It is prepared by a method using either an inorganic acid or an organic acid. As the acid, Malic acid, maleic acid, benzoic acid, ascorbic acid, pamoic acid, succinic acid, bismethy Lensalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, oxalic acid, Lopionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, Ndelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitin Acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzene Sulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, cyclohexyl sulfamic acid, phosphoric acid And nitric acid, but are not limited thereto.   R¹A compound of formula III wherein is hydrogen can be prepared by all routes described below. Wear.                                 Scheme I   R₁A compound of formula III wherein is not hydrogen can be prepared by all routes described below. it can.                                 Scheme II  R_TwoIs a compound of formula III wherein is a hydrogen Protected with a tyl group, it can be prepared by any of the following routes.                               Scheme III   Intermediates of compounds of formula III wherein Y is halogen are prepared by the following route Can be  Specific illustrations of the preparation of representative compounds of the invention are provided in the procedures below.                                 Intermediate 1                 4- (2-chloroethoxy) -benzimidazole   4-hydroxybenzimidazole (75 mL) in tetrahydrofuran (75 mL) 3.1 g, 32.4 mmol), triphenylphosphine (12.75 g, 48.6 mi) Rimol) and 2-chloroethanol (5.2 g, 64.8 mmol) in a solution of At 5 ° C, diethyl azodicarboxylate in tetrahydrofuran (75 mL) (8.5 g, 48.7 mmol) was added over 30 minutes. This mixture The mixture was heated to 23 ° C. and stirred for 48 hours. The solvent was removed under vacuum to give a dark brown oil. I got Chromatography (silica gel, ethyl acetate-1% 2M NH_Three(Methano ) To give 2.9 g (63.8%) of a solid residue. This is ethyl acetate Recrystallization from the title compound afforded the title compound as a white solid. Melting point 153-154 ° C.   Elemental analysis results (C₉H₉ClN_TwoO):   Calculated: C, 54.97; H, 4.61; N, 14.25.   Found: C, 54.86; H, 4.38; N, 14.26.                             Intermediate 2a (n = 1)             2- (2-chloro-ethoxy) -6-nitro-phenylamine   2-amino-3-nitrophenol (32.0 g, 0.208 mol), 1,2-dichloro Loethane (260.0 g, 2.65 mol), potassium carbonate (35.0 g, 0.252 Mo ) And 2-butanone (750 mL) were refluxed for 24 hours. This The mixture was cooled, filtered and the solid was washed with ethyl acetate. Concentrate the filtrate to an oil This was dissolved in ethyl acetate (500 mL). 1N hydroxylation of organic layer Wash with sodium (250 mL), water (500 mL) and brine (2 × 500 mL) And dried over anhydrous magnesium sulfate. Concentrate the filtered solution and remove the residue Trituration with hexane gave 37.8 g (84.6%) of the product as an orange solid. MS (+) PBEI m / e 216/218 (M⁺).   Elemental analysis results (C₈H₉ClN_TwoO_ThreeAs):   Calculated: C, 44.36; H, 4.19; N, 12.93.   Found: C, 44.45; H, 4.02; N, 12.97.   Following this general procedure, utilizing 1,3-dibromopropane, intermediate 2b, That is, 2- (3-bromo-propoxy) -6-nitro-phenylamine is converted to a yellow solid (78.7%). Melting point 88-89 [deg.] C; MS EI m / e 274/276 [ M⁺].   Elemental analysis results (C₉H₁₁BrN_TwoO_ThreeAs):   Calculated: C, 39.29; H, 4.03; N, 10.18.   Found: C, 39.71; H, 3.91; N, 10.27.                                 Intermediate 3a         2- (2-benzylamino-ethoxy) -6-nitro-phenylamine   2- (2-chloroethoxy) -6-nitro-phenylamine (2a3.0 g, 13.8 Mmol) and benzylamine (9.0 g, 84.0 mmol) in 100 parts Heated at １１０110 ° C. for 6 hours. Excess benzylamine is vacuum distilled (70-75 ° C / 0.1 mm). The residue was poured into 1N sodium hydroxide (300 mL), Extracted with ethyl acetate (2 × 300 mL). Combine the organic layers with water (2 x 300 mL) And brine (300 mL). This ethyl acetate layer is dried over anhydrous magnesium sulfate. Dried, filtered and the solvent removed under vacuum to give 5.1 g of a crude red oil. Obtained. Chromatography (silica gel 500 g, ethyl acetate: 2M NH)_Three(Meta Purification in toluene (20: 1) yielded 3.54 g (89.3%) of a red semisolid. Was. 33-60 ° C; MS EI m / e 287 (M⁺).   Elemental analysis results (C_FifteenH₁₇N_ThreeO_ThreeAs):   Calculated: C, 62.71; H, 5.96; N, 14.62.   Found: C, 62.64; H, 6.04; N, 14.23.   According to this general procedure, 4-methyl-benzylamine, thiophen-3-methyl Amine, 1-naphthalenemethylamine, or 1,2,3,4-tetrahydroisox Using Norin,   3b  2- [2- (4-methyl-benzylamino) -ethoxy] -6-nitro-phenyla The min was obtained as a yellow solid (89.0%). 55-57 ° C; EI m / e 3 01 (M⁺).   Elemental analysis results (C₁₆H₁₉N_ThreeO_ThreeAs):   Calculated: C, 63.77; H, 6.36; N, 13.94.   Found: C, 63.32; H, 6.37; N, 13.82.   3c  2-nitro-6- {2-[(thiophen-2-ylmethyl) -amino] -ethoxy}- Phenylamine was obtained as a red semi-solid (88.5%).   Elemental analysis results (C₁₃H_FifteenN_ThreeO_Three(As S):   Calculated: C, 53.23; H, 5.15; N, 14.32.   Found: C, 52.86; H, 4.93; N, 14.15.   3d  2- {2-[(naphthalen-1-ylmethyl) -amino] -ethoxy} -6-nitro- Phenylamine was obtained as a yellow solid (76.3%). Melting point 66-67 ° C; M S EI m / e 337 (M⁺).   Elemental analysis results (C₁₉H₁₉N_ThreeO_ThreeAs):   Calculated: C, 67.64; H, 5.68; N, 12.45.   Found: C, 67.20; H, 5.66; N, 12.26.   3e  2- [2- (3,4-dihydro-1H-isoquinolin-2-yl) -ethoxy] -6- The nitro-phenylamine was obtained as a yellow solid (87.1%). Melting point 95-96 ° C; MS EI m / e 313 (M⁺).   Elemental analysis results (C₁₇H₁₉N_ThreeO_ThreeAs):   Calculated: C, 65.16; H, 6.11; N, 13.41.   Found: C, 64.87; H, 6.11; N, 13.40.   According to this general procedure, 2- (3-bromo-propoxy) -6-nitro-phenyla Min (2b, N = 2) and benzylamine,   3f  Viscous 2- (3-benzylamino-propoxy) -6-nitro-phenylamine Obtained as a fresh orange oil (85.5%). MS EI m / e 301 (M⁺).   Elemental analysis results (C₁₆H₁₉N_ThreeO_ThreeAs):   Calculated: C, 63.77; H, 6.36; N, 13.94.   Found: C, 63.66; H, 6.28; N, 13.89.   According to this general procedure, 4-chloro-2- (2-chloro-ethoxy) -6-nitro-phenyl Enylamine (7) And benzylamine, 4-chloro-benzylamine ,3g  2- (2-benzylamino-ethoxy) -4-chloro-6-nitro-phenyla The min was obtained as an orange-brown solid (54.0%). 87-88 ° C; MS EI  m / e 321/323 (M⁺).   Elemental analysis results (C_FifteenH₁₆ClN_ThreeO_ThreeAs):   Calculated: C, 55.99; H, 5.01; N, 13.06.   Found: C, 55.85; H, 4.90; N, 13.13.   3f  2- [2- (4-chloro-benzylamino) -ethoxy] -4-chloro-6-nitro- Phenylamine was obtained as an orange-brown solid (83.0%). Melting point 116-11 8 ° C.   Elemental analysis results (C₁₃H_FifteenCl_TwoN_ThreeO_TwoAs):   Calculated: C, 50.58; H, 4.24; N, 11.80.   Found: C, 50.65; H, 4.13; N, 11.51.   3i  2- [2- (4-fluoro-benzylamino) -ethoxy] -6-nitro-phenyl The amine was obtained as an orange solid (89.8%). 72-74 ° C.   Elemental analysis results (C_FifteenH₁₆FN_ThreeO_ThreeAs):   Calculated: C, 59.01; H, 5.28; N, 13.76.   Found: C, 58.92; H, 5.16; N, 13.71.3j  2-nitro-6- [2- (4-trifluoromethyl-benzylamino) -ethoxy ] -Phenylamine was obtained as an orange solid (86.7%). 64-66 ° C.   Elemental analysis results (C₁₆H₁₆F_ThreeN_ThreeO_ThreeAs):   Calculated: C, 54.09; H, 4.54; N, 11.83.   Found: C, 53.99; H, 4.33; N, 11.74.   3k  2-nitro-6- [2- (3-phenyl-propylamino) -ethoxy] -phenyl The amine was obtained as a viscous orange oil (83.4%). MS EI m / e 315 ( M⁺).   Elemental analysis results (C₁₇H_{twenty one}N_ThreeO_Three・ 0.25H_TwoO):   Calculated: C, 63.83; H, 6.78; N, 13.14.   Found: C, 63.90; H, 6.56; N, 13.07.                                 Intermediate 4a         3- (2-benzylamino-ethoxy) -benzene-1,2-diamine   2- (2-benzylamino-ethoxy) -6-nitro in ethanol (20 mL) Ro-phenylamine (3a, 0.5 g, 1.74 mmol) and 10% palladium / To a mixture containing carbon (0.1 g) was added hydrazide in ethanol (6.0 mL). A solution of dihydrate (0.6 mL) was added slowly. Heat the reaction to 55-60 ° C Then, the mixture was stirred at that temperature for 16 hours. The mixture was cooled to 25 ° C., filtered and the catalyst Was washed with ethanol. The filtrate was concentrated under vacuum and the residue was taken up in ethyl acetate (100 m L). Wash the organic layer with water (2 × 100 mL) and brine (100 mL) And dried over anhydrous magnesium sulfate, filtered, and the solvent was removed in vacuo to give 38 g (crude yield 85.5%) of the product were obtained as a brown viscous oil. This substance Was used in the next step immediately without further purification.   According to this general procedure, 2- [2- (4-methyl-benzylamino) -ethoxy] -6 -Nitro-phenylamine (3b), 2-nitro-6- {2-[(thiophen-2-ylmethyi) Ru) -amino] -ethoxy} -phenylamine (3c), 2- {2-[(naphthalen-1-yl Methyl) -amino] -ethoxy} -6-nitro-phenylamine (3d), 2- [2- (3,4- Dihydro-1H-isoquinolin-2-yl) -ethoxy] -6-nitro-phenylamido (3e) And 2- (3-benzylamino-propoxy) -6-nitro-phenylamine (3f)   4b  3- [2- (4-methyl-benzylamino) -ethoxy] -benzene-1,2-dia The min was obtained as an off-white solid (79.4%). 77-79 ° C; M S EI m / e 271 (M⁺).   Elemental analysis results (C₁₆H_{twenty one}N_ThreeO):   Calculated: C, 70.82; H, 7.80; N, 15.49.   Found: C, 70.53; H, 7.89; N, 15.50.   4c  3- {2-[(thiophen-2-ylmethyl) -amino] -ethoxy} -benzene-1 , 2-Diamine was obtained as an amber oil (70.0%). MS EI m / e 2 63 (M⁺).   4d  3- {2-[(naphthalen-1-ylmethyl) -amino] -ethoxy} -benzene-1 , 2-Diamine 1/4 hydrate was obtained as a black oil (82.0%). MS EI m / e 307 (M⁺).   Elemental analysis results (C₁₉H_{twenty one}N_ThreeO · 0.25H_TwoO):   Calculated: C, 73.17; H, 6.95; N, 13.47.   Found: C, 73.29; H, 6.86; N, 13.30.   4e  3- [2- (3,4-dihydro-1H-isoquinolin-2-yl) -ethoxy] -ben The zen-1,2-diamine was obtained as a solid (95%). Mp 76-77 ° C. This thing The quality was characterized as dihydrochloride 0.4 hydrate; MS EI m / e 283 ( M⁺).   Elemental analysis results (C₁₇H_{twenty one}N_ThreeO.2HCl.0.4H_TwoO):   Calculated: C, 56.17; H, 6.60; N, 11.56.   Found: C, 56.15; H, 6.68; N, 11.25.   4f  3- (3-benzylamino-propoxy) -benzene-1,2-diamine Obtained as a brown oil. MS EI m / e 271 (M⁺).   Elemental analysis results (C₁₆H_{twenty one}N_ThreeO ・ 0.3H_TwoO):   Calculated: C, 69.44; H, 7.87; N, 15.18.   Found: C, 69.47; H, 7.82; N, 15.30.   According to this general procedure, 2- [2- (4-chloro-benzylamino) -ethoxy] -4 -Chloro-6-nitro-phenylamine (3h), And Rane instead of 10% Pd / C -Using nickel,   4g  3- [2- (4-chloro-benzylamino) -ethoxy] -4-chloro-benzene- 1,2-Diamine was obtained as a light tan solid (75.0%). Melting point 109- 110 ° C.   Elemental analysis results (C_FifteenH₁₇Cl_TwoN_ThreeO):   Calculated: C, 55.23; H, 5.25; N, 12.88.   Found: C, 55.04; H, 5.09; N, 12.62.   4h  3- [2- (4-fluoro-benzylamino) -ethoxy] -benzene-1,2-di The amine was obtained as a white solid (82.4%). 70-71 ° C.   Elemental analysis results (C_FifteenH₁₈FN_ThreeO 0.1H_TwoO):   Calculated: C, 65.12; H, 6.62; N, 15.16.   Found: C, 64.94; H, 6.52; N, 14.93.   4i  3- [2- (4-trifluoromethyl-benzylamino) -ethoxy] -benzene -1,2-Diamine was obtained as a white solid (87.2%). 94-95 ° C.   Elemental analysis results (C₁₆H₁₈F_ThreeN_ThreeO):   Calculated: C, 59.07; H, 5.58; N, 12.92.   Found: C, 58.93; H, 5.24; N, 12.78.   4j  3- [2- (3-phenyl-propylamino) -ethoxy] -benzene-1,2-di The amine was obtained as an oil (76.2%). MS (+) FAB m / e 286 (M + H⁺ ).                                 Intermediate 5a             N- [2- (2-amino-3-nitro-phenoxy) -ethyl]-               N-benzyl-2,2,2-trifluoro-acetamide   2- (2-benzylamino-ethoxy) -6-nitro-phenylamine (3a, 0.50 g, 1.74 mmol), triethylamine (0.50 mL) and methylene chloride (1. Trifluoroacetic anhydride (0.32 mL, 2.26 mmol). Was gradually added. After 2 hours, the reaction was quenched with 1N sodium hydroxide (50 mL) And extracted with methylene chloride. The organic layer was washed with water (2 × 50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under vacuum. To give a crude yellow residue. This substance was crystallized from ethyl acetate-hexane. To give 0.55 g (81.7 g) of a yellow solid. 134-135 ° C; MS EI m / e 383 (M⁺).   Elemental analysis results (C₁₇H₁₆F_ThreeN_ThreeO_FourAs):   Calculated: C, 53.27; H, 4.21; N, 10.96.   Found: C, 53.09; H, 4.35; N, 10.93.   According to this general procedure, 2- (2-benzylamino-ethoxy) -4-chloro-6- Nitro-phenylamine (3g)   5b  N- [2- (2-amino-5-chloro-3-nitro-phenoxy) -ethyl] -N-be Benzyl-2,2,2-trifluoro-acetamide as a yellow solid (76.9%) Obtained. 106-108 ° C; MS (+) FA Bm / e 418/420 (M + H).⁺ .   Elemental analysis results (C₁₇H_FifteenClF_ThreeN_ThreeO_FourAs):   Calculated: C, 48.88; H, 3.62; N, 10.06.   Found: C, 48.96; H, 3.50; N, 10.03.                                 Intermediate 6a           N- [2- (1,2-diamino-benzene-3-yloxy) -ethyl]-               N-benzyl-2,2,2-trifluoro-acetamide   N- [2- (2-amino-3-nitro-phenoxy)-in ethanol (30 mL) Ethyl] -N-benzyl-2,2,2-trifluoro-acetamide (5a0.4 g, 1 0.04 mmol) and 10% palladium on carbon (0.1 g). A solution of hydrazine hydrate (0.6 mL) in ethanol (10.0 mL) was slowly added. added. The reaction was heated to 55-60 ° C and stirred at that temperature for 1 hour. this The mixture was cooled to 25 ° C., filtered and the catalyst was washed with ethanol. Filtrate under vacuum And the residue was diluted with ethyl acetate (100 mL). The organic layer was washed with water (2 × 100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, Filter and remove the solvent under vacuum to give 0.32 g (87.5% crude yield) of the product as a brown As a viscous oil. MS (+) FA Bm / e 354 (M + H)⁺.   This general procedure allows N- [2- (2-amino-5-chloro-3-nitro-phenoxy) C) -Ethyl] -N-benzyl-2,2,2-trifluoro-acetamide (5b) hand,   6b  N-benzyl-N- [2- (2,3-diamino-5-chloro-phenoxy) -ethyl] -2,2,2-trifluoro-acetamide as a brown viscous oil (91.3%) Obtained. MS EI m / e 387/389 (M⁺).   Elemental analysis results (C₁₇H₁₇ClF_ThreeN_ThreeO_TwoAs):   Calculated: C, 52.65; H, 4.42; N, 10.84.   Found: C, 52.47; H, 4.39; N, 10.90.                                 Intermediate 7         4-chloro-2- (2-chloro-ethoxy) -6-nitro-phenylamine   2- (2-chloro-ethoxy) -6-nitro-phenylamine (2a, 30.0 g, 0.1 14 mol), a solution of N-chlorosuccinamide and acetonitrile (1.3 L). Refluxed for 4 hours. The mixture is concentrated under vacuum and the residue is taken up in ethyl acetate (500 mL) Diluted. The organic layer was washed with water (2 × 250 mL) and brine (250 mL), Dry over anhydrous magnesium sulfate, filter, remove the solvent under vacuum and remove the orange A solid residue was obtained. Crystallized from ethyl acetate-hexane, 33.5 g (95. 3%) as an orange solid. Melting point 109-110 ° C; MS EI m / e 2 50/252/254 (M⁺).   Elemental analysis results (C₈H₈Cl_TwoN_TwoO_ThreeAs):   Calculated: C, 38.27; H, 3.21; N, 11.16.   Found: C, 38.15; H, 3.10; N, 10.96.                                 Example 1   [2- (1H-benzimidazol-4-yloxy) -ethyl] -benzyl-amine   4- (2-chloroethoxy) -benzimidazole (10.39 g, 1.98 mm Mol) and benzylamine (9 mL) at 100-110 ° C. for 3.5 hours did. The solvent was concentrated under vacuum (50-60 ° C./0.1 mm) and 1N sodium hydroxide (50 mL) and extracted with ethyl acetate (2 × 50 mL). Combined organic Wash with water (100 mL) and brine (100 mL) and dry over anhydrous magnesium sulfate. Dry, filter and remove the solvent under vacuum to give 0.58 g of a viscous yellow oil. Was. Chromatography (silica gel 60 g, methylene chloride-0.5% 2M NH)_Three (In methanol)) to give 0.364 g (68.7%) of a yellow oil. This Was dissolved in an ethyl acetate-methanol mixture and treated with excess hydrogen chloride. Afforded the title compound (0.38 g, 58.5%) as a white solid. Melting point 256- 259 ° C (decomposition); MS EI m / e 267 (M⁺).   Elemental analysis results (C₁₆H₁₇N_ThreeO.2HCl.0.5H_TwoO):   Calculated: C, 55.02; H, 5.77; N, 12.03.   Found: C, 55.26; H, 5.69; N, 12.03.                                 Example 2                         Benzyl- [2- (2-methyl-           1H-benzimidazol-4-yloxy) -ethyl] -amine   3- (2-benzylamino-ethoxy) -benzene-1,2-diamine (4a, 0.35 g, 1.36 mmol) and acetic acid (10 mL) was refluxed for 14 hours. Solvent Concentrate under vacuum (50-60 ° C / 0.1mm) and dissolve the residue in ethyl acetate (50mL) did. The organic layer was washed with 1N sodium hydroxide (50 mL), water (100 mL) and brine. (100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was removed in vacuo. Removed underneath to give the crude base. Chromatography (silica gel 35 g, vinegar Ethyl acid-1% 2M NH_Three(In methanol)) to give 0.29 g of pure base ( 76.3%) as a tan solid foam. Ethyl acetate-methanol And treated with an excess of 1N hydrogen chloride to give the title compound (0.33 g, (90.0%) as a white solid. Melting point> 250 ° C .; MS EI m / e 28 1 (M⁺).   Elemental analysis results (C₁₇H₁₉N_ThreeO.2HCl):   Calculated: C, 57.63; H, 5.97; N, 11.61.   Found: C, 57.23; H, 5.89; N, 12.86.                                 Example 3                   Benzyl- [2- (2-trifluoromethyl-           1H-benzimidazol-4-yloxy) -ethyl] -amine   N- [2- (1,2-diamino-benzene-3-yloxy) -ethyl] -N-benzyl-2, 2,2-trifluoro-acetamide (6a1.0 g, 2.83 mmol) and A solution of trifluoroacetic acid (10 mL) was refluxed for 4 hours. The solvent is removed under vacuum (50-60 C./0.1 mm) and the residue was dissolved in ethyl acetate (150 mL). Organic layer 1N sodium hydroxide (50 mL), water (100 mL) and brine (100 mL) Wash, dry over anhydrous magnesium sulfate, filter, remove the solvent under vacuum, A viscous oil residue was obtained. Chromatography (140 g silica gel, Chill-hexane-2M NH_Three(In methanol) (10: 10: 1)) to give 0.8 6 g (70.7%) of N-benzyl-2,2,2-trifluoro-N- [2- (trifluoro Methyl-1H-benzomidazol-4-yloxy) -ethyl] -acetamide is tan As a solid foam. MS EI m / e 431 (M⁺).   N-benzyl-2,2,2-trifluoro-N- [2- (trifluoromethyl-1H-ben Zoimidazol-4-yloxy) -ethyl] -acetamide (0.78 g, 1.80 mi) Mixture of 6% methanol aqueous solution (35 mL) and potassium carbonate (1.7 g) The material was refluxed for 3 hours. Cool the mixture to 25 ° C. and pour into water (200 mL) And extracted with ethyl acetate (3 × 150 mL). The organic layer was washed with water (200 mL) and salt. Wash with water (200 mL), dry over anhydrous magnesium sulfate, filter and remove the solvent. Removal under air afforded a solid residue. Crystallize this material from ethyl acetate 0.50 g (83.5%) of benzyl- [2- (2-trifluoromethyl-1H-benzo) Imidazol-4-yloxy) -ethyl] -amine · 0.25 ethyl acetate was added to a white solid. Obtained as a form. 130-131 ° C; MS EI m / e 335 (M⁺).   Elemental analysis results (C₁₇H₁₆F_ThreeN_ThreeO 0.25C_FourH₈O_TwoAs):   Calculated: C, 60.50; H, 5.08; N, 11.76.   Found: C, 60.54; H, 4.95; N, 11.72.   Benzyl- [2- (2-trifluoromethyl-1H-benzimidazol-4-ylo Xy) -ethyl] -amine · 0.25 ethyl acetate (0.40 g, 2.61 mmol) in vinegar Dissolve in ethyl acetate-methanol mixture and treat with excess 1N hydrogen chloride to give the title The compound (0.35 g, 79.1%) was obtained as a white solid. Melting point 194-195 ° C; MS EI m / e 335 (M⁺).   Elemental analysis results (C₁₇H₁₉N_Three(As O.HCl):   Calculated: C, 57.63; H, 5.97; N, 11.61.   Found: C, 57.23; H, 5.89; N, 12.86.                                 Example 4             (4-methyl-benzyl)-[2- (2-trifluoromethyl-           1H-benzimidazol-4-yloxy) -ethyl] -amine   Example2According to the general procedure used in the above, 3- [2- (4-methyl-benzylamino)- Ethoxy] -benzene-1,2-diamine (4b) And trifluoroacetic acid , (4-Methyl-benzyl)-[2- (2-trifluoromethyl-1H-benzimidazo) Ethyl-4-yloxy) -ethyl] -amine.0.25 ethyl acetate was added to a white solid (60 .5%). Mp 154-158 ° C; MS EI m / e 349 (M⁺).   Elemental analysis results (C₁₈H₁₈F_ThreeN_ThreeO 0.25C_FourH₈O_TwoAs):   Calculated: C, 61.45: H, 5.43; N, 11.31.   Found: C, 61.47; H, 5.40; N, 11.27.   (4-Methyl-benzyl)-[2- (2-trifluoromethyl-1H-benzimidazo L-4-yloxy) -ethyl] -amine dihydrochloride as a white solid (90.1%) Obtained. 230-233 ° C; MS EI m / e 349 (M⁺).   Elemental analysis results (C₁₈H₁₈F_ThreeN_ThreeO.2HCl):   Calculated: C, 51.20; H, 4.77; N, 9.95.   Found: C, 50.92; H, 4.69; N, 9.89.                                 Example 5     [2- (2-benzyl-1H-benzimidazol-4-yloxy) -ethyl]-                         (4-methyl-benzyl) -amine   Example2According to the general procedure used in the above, 3- [2- (4-methyl-benzylamino)- Ethoxy] -benzene-1,2-diamine (4b) And phenylacetic acid, 2- (2-benzyl-1H-benzimidazol-4-yloxy) -ethyl]-(4-methyl (Benzyl) -amine dihydrochloride was obtained as a white solid (65.8%). Melting point> 2 50 ° C .; MS EI m / e 371 (M⁺).   Elemental analysis results (C_{twenty four}H_{twenty five}N_ThreeO.2HCl):   Calculated: C, 64.86; H, 6.12; N, 9.46.   Found: C, 64.43; H, 6.15; N, 9.31.                                 Example 6   (4-Methyl-benzyl)-{2- [2- (1,1,2,2,2-pentafluoro-ethyl)-           1H-benzimidazol-4-yloxy] -ethyl} -amine   Example2According to the general procedure used in the above, 3- [2- (4-methyl-benzylamino)- Ethoxy] -benzene-1,2-diamine (4b) And pentafluoropropionic acid Using   (4-methyl-benzyl)-{2- [2- (1,1,2,2,2-pentafluoro-ethyl) -1 H-benzimidazol-4-yloxy] -ethyl} -amine 1.25 hydrate as white As a solid (75.3%). 85-90 ° C (decomposition); MS EI m / e  399 (M⁺).   Elemental analysis results (C₁₉H₁₈F_FiveN_ThreeO 1.25H_TwoO):   Calculated: C, 54.09; H, 4.90; N, 9.96.   Found: C, 53.83; H, 4.65; N, 9.76.   (4-methyl-benzyl)-{2- [2- (1,1,2,2,1-pentafluoro-ethyl) -1 H-benzimidazol-4-yloxy] -ethyl} -amine hydrochloride was converted to a white solid ( 79.7%). Melting point 180 [deg.] C (decomposition); MS EI m / e 399 (M⁺).   Elemental analysis results (C₁₉H₁₈F_FiveN_Three(As O.HCl):   Calculated: C, 52.36; H, 4.39; N, 9.64.   Found: C, 52.23; H, 4.31; N, 9.54.                                 Example 7           Thiophene-2-ylmethyl- [2- (2-trifluoromethyl-           1H-benzimidazol-4-yloxy) -ethyl] -amine   Example2According to the general procedure used in the above, 3- {2-[(thiophen-2-ylmethyl) -Amino] -ethoxy} -benzene-1,2-diamine (4c) And trifluoroacetic acid Use   Thiophene-2-ylmethyl- [2- (2-trifluoromethyl-1H-benzimidida Zol-4-yloxy) -ethyl] -amine 1.6 hydrochloride was converted to a tan solid (58. 3%). Melting point 184 [deg.] C; MS EI m / e 341 (M⁺).   Elemental analysis results (C₁₈H₁₈F_ThreeN_ThreeO. 1.6 HCl):   Calculated: C, 44.98; H, 4.04; N, 10.38.   Found: C, 44.99; H, 4.05; N, 10.33.                                 Example 8                   Benzyl- [3- (2-trifluoromethyl-         1H-benzimidazol-4-yloxy) -propyl] -amine   Example2According to the general procedure used in the above, 3- (3-benzylamino-propoxy)- Benzene-1,2-diamine (4f) And trifluoroacetic acid,   Benzyl- [3- (2-trifluoromethyl-1H-benzimidazol-4-ylo Xy) -propyl] -amine 1/2 hydrate as a tan solid foam (57.6%) Obtained. Melting point 50-70 ° C; MS EI m / e 349 (M⁺).   Elemental analysis results (C₁₈H₁₈F_ThreeN_Three(As O-0.5H2O):   Calculated: C, 60.33; H, 5.34; N, 11.73.   Found: C, 60.34; H, 5.30; N, 11.84.   Benzyl- [3- (2-trifluoromethyl-1H-benzimidazol-4-ylo Xy) -propyl] -amine dihydrochloride was obtained as a white solid (98.0%). Melting point 194-197 ° C; MS EI m / e 349 (M⁺).   Elemental analysis results (C₁₈H₁₈F_ThreeN_ThreeO.2HCl):   Calculated: C, 51.20; H, 4.77; N, 9.95.   Found: C, 51.09; H, 4.49; N, 9.86.                                 Example 9         Benzyl- {2- [2- (1,1,2,2,2-pentafluoro-ethyl)-           1H-benzimidazol-4-yloxy] -ethyl} -amine   Example3The N- [2- (1,2-diamino-benzene-3 -Yloxy) -ethyl] -N-benzyl-2,2,2-trifluoro-acetamide (6a ) And pentafluoropropionic acid   Benzyl- {2- [2- (1,1,2,2,2-pentafluoro-ethyl) -1H-benzoi Midazol-4-yloxy] -ethyl} -amine as a white solid (59.8%) Obtained. 152-153 ° C; MS EI m / e 385 (M +).   Elemental analysis results (C₁₈H₁₆F_FiveN_ThreeO):   Calculated: C, 56.11; H, 4.19; N, 10.91.   Found: C, 56.02; H, 4.10; N, 10.73.   Benzyl- {2- [2- (1,1,2,2,2-pentafluoro-ethyl) -1H-benzoi Midazol-4-yloxy] -ethyl} -amine hydrochloride 0.75 hydrate was added to a white solid. Obtained as the form (69.4%). 120-135 ° C; MS (+) ESI m / e 3 86 (M + H⁺).   Elemental analysis results (C₁₈H₁₆F_FiveN_ThreeO ・ HCl ・ 0.75H_TwoO):   Calculated: C, 49.67; H, 4.28; N, 9.65.   Found: C, 49.88; H, 3.95; N, 9.66.                                 Example 10           Naphthalen-1-ylmethyl- [2- (2-trifluoromethyl-           1H-benzimidazol-4-yloxy] -ethyl] -amine   Example2According to the general procedure used in the above, 3- {2-[(naphthalen-1-ylmethyl) -Amino] -ethoxy} -benzene-1,2-diamine (4d) And trifluoroacetic acid Use   Naphthalen-1-ylmethyl- [2- (2-trifluoromethyl-1H-benzimidida Zol-4-yloxy] -ethyl] -amine was obtained as a white solid (63.1%). . 130-133 ° C; MS EI 385 m / e (M⁺).   Elemental analysis results (C_{twenty one}H₁₈F_ThreeN_ThreeO):   Calculated: C, 65.45; H, 4.71; N, 10.90.   Found: C, 65.28; H, 4.43; N, 10.57.   Naphthalen-1-ylmethyl- [2- (2-trifluoromethyl-1H-benzimidida Zol-4-yloxy] -ethyl] -amine hydrochloride as a white solid (94.8%). I got it. Melting point 208-209 ° C; MS EI m / e 385 (M⁺).   Elemental analysis results (C₁₈H₁₈F_ThreeN_Three(As O.HCl):   Calculated: C, 59.79; H, 4.54; N, 9.96.   Found: C, 59.39; H, 4.45; N, 9.81.                                 Example 11                         Thiophene-2-ylmethyl-         [2- (1H-benzimidazol-4-yloxy) -ethyl] -amine   Example2According to the general procedure used in the above, 3- {2-[(thiophen-2-ylmethyl) -Amino] -ethoxy} -benzene-1,2-diamine (4c) And formic acid, Thiophene-2-ylmethyl- [2- (1H-benzimidazol-4-yloxy) -d [Tyl] -amine 1/4 hydrate was obtained as a viscous yellow oil (63.2%). MS  EI m / e 273 (M⁺).   Elemental analysis results (C₁₄H_FifteenN_ThreeOS-0.25H_TwoO):   Calculated: C, 60.52; H, 5.62; N, 15.12.   Found: C, 60.85; H, 5.49; N, 15.39.   Thiophene-2-ylmethyl- [2- (1H-benzimidazol-4-yloxy)- Ethyl] -amine dihydrochloride hemihydrate was obtained as a white solid (69.2%). 248-252 ° C (dec); MS EI m / e 273 (M⁺).   Elemental analysis results (C₁₄H_FifteenN_ThreeOS ・ 2.0HCl ・ 0.5H_TwoO):   Calculated: C, 47.33; H, 5.11; N, 11.83.   Found: C, 46.95; H, 5.13; N, 11.73.                                 Example 12                           (4-methyl-benzyl)-           {2- [2- (1,1,2,2,3,3,3-heptafluoro-propyl)-           1H-benzimidazol-4-yloxy] -ethyl} -amine   Example2According to the general procedure used in the above, 3- [2- (4-methyl-benzylamino)- Ethoxy] -benzene-1,2-diamine (4b) And heptafluorobutyric acid hand,   (4-Methyl-benzyl)-{2- [2- (1,1,2,2,3,3,3-heptafluoro-pro Pyl) -1H-benzimidazol-4-yloxy] -ethyl} -amine was converted to a white solid. (63.7%). Melting point 144-146 [deg.] C; MS EI m / e 449 ( M⁺).   Elemental analysis results (C₂₀H₁₈F₇N_ThreeO):   Calculated: C, 53.46; H, 4.04; N, 9.35.   Found: C, 53.23; H, 3.69; N, 9.11.   (4-Methyl-benzyl)-{2- [2- (1,1,2,2,3,3,3-heptafluoro-pro Pyl) -1H-benzimidazol-4-yloxy] -ethyl} -amine.1.5 hydrochloride As a white solid (87.6%). Melting point 198-199.5 [deg.] C; MS EI m / e 449 (M⁺).   Elemental analysis results (C₁₉H₁₈F_FiveN_ThreeO. 1.5 HCl):   Calculated: C, 47.66; H, 3.90; N, 8.34.   Found: C, 47.47; H, 3.76; N, 8.24.                                 Example 13   2- [2- (2-trifluoromethyl-1H-benzimidazol-4-yloxy-               Ethyl] -1,2,3,4-tetrahydro-isoquinoline   Example2According to the general procedure used in the above, 3- [2- (3,4-dihydro-1H-isox Norin-2-yl) -ethoxy] -benzene-1,2-diamine (4e) And Trifluo Using acetic acid,   2- [2- (2-trifluoromethyl-1H-benzimidazol-4-yloxy)- Ethyl] -1,2,3,4-tetrahydro-isoquinoline 1/4 hydrate as white solid (95.8%). Mp 168-171 ° C; MS EI m / e 361 (M⁺) .   Elemental analysis results (C₁₉H₁₈F_ThreeN_ThreeO · 0.25H_TwoO):   Calculated: C, 62.37; H, 5.10; N, 11.49.   Found: C, 62.52; H, 4.85; N, 11.50.   2- [2- (2-trifluoromethyl-1H-benzimidazol-4-yloxy)- Ethyl] -1,2,3,4-tetrahydro-isoquinoline dihydrochloride was added to a white solid (94 .3%). Melting point 210-214 ° C (decomposition); MS EI m / e 361 (M⁺ ).   Elemental analysis results (C₁₉H₁₈F_ThreeN_ThreeO.2HCl):   Calculated: C, 52.55; H, 4.64; N, 9.68.   Found: C, 52.20; H, 4.81; N, 9.33.                                 Example 14               Benzyl- [2- (6-chloro-2-trifluoromethyl-           1H-benzimidazol-4-yloxy) -ethyl-amine   Example3According to the general procedure used in the above, N-benzyl-N- [2- (2,3-diamino -5-chloro-phenoxy) -ethyl] -2,2,2-trifluoro-acetamide (6b) And using trifluoroacetic acid,   Benzyl- [2- (6-chloro-2-trifluoromethyl-1H-benzimidazole- 4-yloxy) -ethyl-amine was obtained as a white solid (76.4%). Melting point 1 71-172 ° C; MS EI m / e 369 (M⁺).   Elemental analysis results (C₁₇H_FifteenClF_ThreeN_ThreeO):   Obituaries: C, 55.22; H, 4.09; N, 11.36   Found: C, 55.05; H, 3.91; N, 11.13.   Benzyl- [2- (6-chloro-2-trifluoromethyl-1H-benzimidazole- 4-yloxy) -ethyl-amine was obtained as a white solid (73.4%). Melting point 2 10-212 ° C; MS EI m / e 369 (M⁺).   Elemental analysis results (C₁₇H_FifteenClF_ThreeN_Three(As O.HCl):   Calculated: C, 50.26; H, 3.97; N, 10.34.   Found: C, 50.29; H, 3.81; N, 10.32.                                 Example 15         4-chloro-benzyl- [2- (6-chloro-2-trifluoromethyl-           1H-benzimidazol-4-yloxy) -ethyl-amine   Example2According to the general procedure used in the above, 3- [2- (4-chloro-benzylamino)- Ethoxy] -4-chloro-benzene-1,2-diamine (4g) And trifluoroacetic acid Using   4-chloro-benzyl- [2- (6-chloro-2-trifluoromethyl-1H-benzoy Midazol-4-yloxy) -ethyl-amine fumarate was converted to a light gray solid ( 79.6%). Melting point 191-193 [deg.] C; MS EI m / e 403/40. 5/407 (M⁺).   Elemental analysis results (C₁₇H₁₄Cl_ThreeF_ThreeN_ThreeOC_FourH_FourO_FourAs):   Calculated: C, 48.48; H, 3.49; N, 8.08.   Found: C, 48.17; H, 3.26; N, 8.11.                                 Example 16           (4-fluoro-benzyl) -2- [2- (2-trifluoromethyl-           1H-benzimidazol-4-yloxy) -ethyl] -amine   Example2According to the general procedure used in the above, 3- [2- (4-fluoro-benzylamino) ) -Ethoxy] -benzene-1,2-diamine (4h) And trifluoroacetic acid hand,   (4-Fluoro-benzyl) -2- [2- (2-trifluoromethyl-1H-benzimidida Zol-4-yloxy) -ethyl] -amine hydrochloride 1/2 hydrate was converted to a white solid (5 0.4%). Mp 225-227 ° C; MS EI m / e 353 (M⁺).   Elemental analysis results (C₁₇H_FifteenF_FourN_ThreeO ・ 1.0HCl ・ 0.5H_TwoO):   Calculated: C, 51.20; H, 4.30; N, 10.54.   Found: C, 51.06; H, 3.93; N, 10.35.                                 Example 17     [2- (2-trifluoromethyl-1H-benzimidazol-4-yloxy)-               Ethyl]-(4-trifluoromethyl-benzyl) -amine   Example2According to the general procedure used in the above, 3- [2- (4-trifluoromethyl-benzene) (Dilamino) -ethoxy] -benzene-1,2-diamine (4i) And trifluorovinegar Utilizing acid   [2- (2-trifluoromethyl-1H-benzimidazol-4-yloxy) -ethyl L]-(4-Trifluoromethyl-benzyl) -amine hydrochloride was added to a white solid (80.5). %). MS (+) FAB m / e 404 (M + H⁺ ).   Elemental analysis results (C₁₈H_FifteenF₆N_ThreeO. 1.0 HCl):   Calculated: C, 49.16; H, 3.67; N, 9.55.   Found: C, 49.21; H, 3.50; N, 9.46.                                 Example 18             (3-phenyl-propyl)-[2- (2-trifluoromethyl-           1H-benzimidazol-4-yloxy) -ethyl] -amine   Example2According to the general procedure used in the above, 3- [2- (3-phenyl-propylamino ) -Ethoxy] -benzene-1,2-diamine (4j) And trifluoroacetic acid hand,   (3-phenyl-propyl)-[2- (2-trifluoromethyl-1H-benzimidazo Yl-4-yloxy) -ethyl] -amine hydrochloride as a white solid (88.7%) Obtained. MS (+) FAB m / e 364 (M + H⁺).   Elemental analysis results (C₁₉H₂₀F_ThreeN_ThreeO. 1.0 HCl):   Calculated: C, 57.07; H, 5.29; N, 10.51.   Found: C, 56.89; H, 5.15; N, 10.28.                                   Pharmacology   The compounds of the present invention are dopamine autoreceptor agonists. That is, they Helps regulate the synthesis and release of the nervous system transmitter dopamine. Thus, These include disorders of the dopamine system such as schizophrenia, Parkinson's disease and It is useful for treating Rett syndrome and the like. Such drugs include post-synaptic dopamine D_Two Is a partial agonist at the receptor and is therefore Useful for treatment.   The affinity for dopamine autoreceptors was determined by Seemen and Schaus aus), European Journal of Pharmacology (European Journal of Pharmacology), 203, 105-109, 1991. . In this method, homogenized rat striatal brain tissue is^ThreeH-Quinpyrrole (Quin. ) And various concentrations of the test compound, filtered, washed, and Count on a Betaplate scintillation counter.   Dopamine D_TwoThe high affinity for the receptor is described by Fields et al., Brain et al. Research (BrainRes.),136, 578 (1977) and Yamamura et al., NeuroTransmi Neurotransmitter Receptor Binding, Raven Press, N.Y. (1978) Was. In this method, homogenized limbic brain tissue is^ThreeH-spiroperidol (Spiper.) And with various concentrations of the test compound, filtered, washed, and Hydrofluor scintillation cocktail (National Diamond) Shake with Gnostics (National Diagnostics), Packard 46 Count with a 0CD scintillation counter.   The results of tests using representative compounds of the present invention are shown in the table below.  Thus, the compounds of the present invention effect the synthesis of the nervous system transmitter dopamine, thus Schizophrenia, Parkinson's disease, Tourette's syndrome, alcohol addiction, Useful for treatment of dopamine disorders such as Cain addiction and addiction to similar drugs It is.   Solid carriers applicable to pharmaceutical compositions containing the compound of the present invention include flavoring agents , Lubricants, solubilizers, suspending agents, fillers, fluidizers, compression aids, binders or tablets One or more substances or encapsulating materials that can also act as disintegrants Can be mentioned. In powders, the carrier is a finely divided solid, It is mixed with finely ground active ingredient. For tablets, the active ingredient Required Mixed in a suitable ratio with a carrier having excellent compression properties, and compressed to the desired shape and dimensions. Molded. The powders and tablets preferably contain up to 99% of the active ingredient. . Suitable solid carriers include, for example, calcium phosphate, magnesium stearate. Um, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, Methylcellulose, sodium carboxymethylcellulose, polyvinylpyrroli Gin, low melting waxes and ion exchange resins.   Liquid carriers form solutions, suspensions, emulsions, syrups and elixirs It may be used for The active ingredient of the present invention may be water, an organic solvent, a mixture of both, or a medicament. Dissolving or suspending in a pharmaceutically acceptable liquid carrier such as a pharmaceutically acceptable fat or oil Can be. Liquid carriers include solubilizers, emulsifiers, buffering agents, preservatives, sweeteners, flavoring agents , Suspending agents, thickeners, coloring agents, viscosity regulators, stabilizers or osmotic pressure regulators Can be included. Liquid for oral and parenteral administration Suitable examples of the carrier include water (particularly an additive as described above (e.g., cellulose-derived Body, preferably sodium carboxymethylcellulose solution)), Coal (including monohydric and polyhydric alcohols (e.g., glycols)) And their derivatives, and oils such as fractionated coconut and peanut oils. You. For parenteral administration, carriers include ethyl oleate and isopromyristate. It can also be an oily ester such as a pill. Sterile liquid carrier for parenteral administration Used in sterile liquid compositions.   Liquid pharmaceutical compositions that are sterile solutions or suspensions can be, for example, intramuscular, intraperitoneal or intramuscular. Alternatively, it can be used by subcutaneous injection. Sterile solutions should be administered intravenously. Can also be. Oral administration can be in either liquid or solid composition form .   The pharmaceutical composition is preferably in unit dosage form (eg, a tablet or capsule). Good. In such form, the composition is administered in unit dosage form containing an appropriate amount of the active ingredient. Subdivided into quantities. The unit dosage form can contain the packaged composition (e.g., , Ampules, filled syringes or liquid-containing medicine bags). Unit agent The form can be, for example, a capsule or tablet itself, or Such compositions can be in any number of packaging forms.   The dose to be used in the treatment of a particular mental illness must be subjectively determined by the attending physician. Must. Relevant variables include specific mental illness and patient physique, age and And response patterns.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/16 A61P 25/16 25/18 25/18 25/30 25/30 43/00 111 43/00 111 C07D 235/08 C07D 235/08 235/10 235/10 401/12 401/12 409/12 409/12 (81) Designated country EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG) , AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, R, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, HU, IL, IS, JP, KE, KG, KP, KR, KZ, LC , LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW (72) Inventor Mushaw, Richard Eric United States 08540 Boxwood Drive, Princeton, NJ 21, No. 21

Claims (1)

[Claims] 1. Formula I: Wherein R ¹ is hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, a straight or branched chain alkyl group having up to 6 carbon atoms, or, if desired, halogen, amino, nitro, hydroxy, C ₁ -C benzyl which may optionally be substituted with one to three substituents selected from ₆ alkoxy; R ² is hydrogen or C ₁ -C ₆ alkyl; R ³ is hydrogen, straight up to 10 carbon atoms chain or branched chain alkyl group, cyclohexylmethyl or - (CH _{2) m} Ar (wherein, Ar is phenyl, thienyl, furanyl or pyridinyl, each optionally, halogen, C ₁ -C ₆ alkoxy, may be substituted with one to two substituents selected from trifluoromethyl or C ₁ -C ₆ alkyl); or, NR ² R ³ is 1,2,3,4 Phosphorus-1-yl or 1,2,3,4-tetrahydroisoquinolin-2-yl; Y = halogen, lower alkyl, amino, and lower alkoxy; n = 1 to 5] or a pharmaceutically acceptable compound thereof. Salt. 2. The compound according to claim 1, wherein R ² is benzyl, substituted benzyl, thienylmethyl, tetrahydroisoquinoline, furanylmethyl, phenylbutyl, cyclohexylmethyl or 4-fluorobutyrophenone, and R ¹ is trifluoromethyl or tetrafluoroethyl. 3. The compound according to claim 1, which is [2- (1H-benzimidazol-4-yloxy) -ethyl] -benzyl-amine, or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1, which is benzyl- [2- (2-methyl-1H-benzimidazol-4-yloxy) -ethyl] -amine, or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 1, which is benzyl- [2- (2-trifluoromethyl-1H-benzimidazol-4-yloxy) -ethyl] -amine, or a pharmaceutically acceptable salt thereof. 6. The compound according to claim 1, which is (4-methyl-benzyl)-[2- (2-trifluoromethyl-1H-benzimidazol-4-yloxy) -ethyl] -amine, or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 1, which is [2- (2-benzyl-1H-benzimidazol-4-yloxy) -ethyl]-(4-methyl-benzyl) -amine, or a pharmaceutically acceptable salt thereof. 8. (4-methyl-benzyl)-{2- [2- (1,1,2,2,2-pentafluoro-ethyl) -1H-benzimidazol-4-yloxy] -ethyl} -amine. Or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 1, which is thiophen-2-ylmethyl- [2- (2-trifluoromethyl-1H-benzimidazol-4-yloxy) -ethyl] -amine, or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 1, which is benzyl- [3- (2-trifluoromethyl-1H-benzimidazol-4-yloxy) -propyl] -amine, or a pharmaceutically acceptable salt thereof. 11. The compound according to claim 1, which is benzyl- {2- [2- (1,1,2,2,2, pentafluoro-ethyl) -1H-benzimidazol-4-yloxy] -ethyl} -amine or a pharmaceutically acceptable salt thereof. Acceptable salt. 12. 12. The compound according to claim 1, which is naphthalen-1-ylmethyl- [2- (2-trifluoromethyl-1H-benzimidazol-4-yloxy] -ethyl] -amine, or a pharmaceutically acceptable salt thereof. 12. The compound according to claim 1, which is 2--2-ylmethyl- [2- (1H-benzimidazol-4-yloxy) -ethyl] -amine, or a pharmaceutically acceptable salt thereof. 14. (4-Methyl-benzyl)- The compound according to claim 1, which is {2- [2- (1,1,2,2,3,3,3-heptafluoro-propyl) -1H-benzimidazol-4-yloxy] -ethyl} -amine. 15. A pharmaceutically acceptable salt thereof 15.2-[2- (2-trifluoromethyl-1H-benzimidazol-4-yloxy-ethyl] -1,2,3,4-tetrahydro-isoquinoline. Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which is-(6-chloro-2-trifluoromethyl-1H-benzimidazol-4-yloxy) -ethyl-amine, or a pharmaceutically acceptable salt thereof. 18. The compound according to claim 1, which is [2- (6-chloro-2-trifluoromethyl-1H-benzimidazol-4-yloxy) -ethyl-amine, or a pharmaceutically acceptable salt thereof. The compound according to claim 1, which is -benzyl) -2- [2- (2-trifluoromethyl-1H-benzimidazol-4-yloxy) -ethyl] -amine, or a pharmaceutically acceptable salt thereof. The compound according to claim 1, which is-(2-trifluoromethyl-1H-benzimidazol-4-yloxy) -ethyl]-(4-trifluoromethyl-benzyl) -amine, or a pharmaceutically acceptable salt thereof. . (3-phenyl-propyl)-[ - (2-trifluoromethyl--1H- benzoimidazol-4-yloxy) - ethyl] -. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein an amine with 21. dopamine D ₂ agonist treatment A method of treating a disease in a mammal that responds to a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a formula: Wherein R ¹ is hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, a straight or branched chain alkyl group having up to 6 carbon atoms, or, if desired, halogen, amino, nitro, hydroxy, C ₁ -C ₆ alkoxy and C ₁ -C ₆ benzyl which may be substituted with 1-3 substituents selected from alkyl; R ² is hydrogen or C ₁ -C ₆ alkyl; R ³ is hydrogen A straight or branched chain alkyl group having up to 10 carbon atoms, cyclohexylmethyl or — (CH ₂ ) _m Ar, where Ar is phenyl, thienyl, furanyl or pyridinyl, each optionally being halogen, C ₁ -C ₆ alkoxy, optionally substituted with one to two substituents selected from trifluoromethyl or C ₁ -C ₆ alkyl); or, NR ² R ³ is 1,2, 3,4-tetrahydroquinolin-1-yl or 1,2,3,4-tetrahydroisoquinolin-2-yl; Y = halogen, lower alkyl, amino, and lower alkoxy; n = 1 to 5]; Administering a pharmaceutically acceptable salt thereof. 22. 22. The method of claim 21, wherein the disease to be treated is schizophrenia. 23. 22. The method according to claim 21, wherein the disease to be treated is Parkinson's disease. 24. 22. The method according to claim 21, wherein the disease to be treated is Tourette's syndrome. 25. 22. The method according to claim 21, wherein the disease to be treated is drug addiction or alcohol addiction. 26. A pharmaceutically acceptable carrier and a therapeutically effective amount of the formula: Wherein R ¹ is hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, a straight or branched chain alkyl group having up to 6 carbon atoms, or, if desired, halogen, amino, nitro, hydroxy, C ₁ -C benzyl which may optionally be substituted with one to three substituents selected from ₆ alkoxy; R ² is hydrogen or C ₁ -C ₆ alkyl; R ³ is hydrogen, straight up to 10 carbon atoms A chain or branched chain alkyl group, cyclohexylmethyl or — (CH ₂ ) _m Ar, where Ar is phenyl, thienyl, furanyl or pyridinyl, each optionally being halogen, C ₁ -C ₆ alkoxy, NR ² R ³ may be substituted with one or two substituents selected from trifluoromethyl or C ₁ -C ₆ alkyl); Nolin-1-yl or 1,2,3,4-tetrahydroisoquinolin-2-yl; Y = halogen, lower alkyl, amino, and lower alkoxy; n = 1 to 5] or a pharmaceutically acceptable compound thereof. A pharmaceutical composition comprising: