AU746717B2 - 4-aminoalkoxy-1H-benzimidazole derivatives, their preparation and their use as dopamine autoreceptor (D2) agonists - Google Patents

4-aminoalkoxy-1H-benzimidazole derivatives, their preparation and their use as dopamine autoreceptor (D2) agonists Download PDF

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AU746717B2
AU746717B2 AU59153/98A AU5915398A AU746717B2 AU 746717 B2 AU746717 B2 AU 746717B2 AU 59153/98 A AU59153/98 A AU 59153/98A AU 5915398 A AU5915398 A AU 5915398A AU 746717 B2 AU746717 B2 AU 746717B2
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ethyl
benzyl
yloxy
trifluoromethyl
pharmaceutically acceptable
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Richard Eric Mewshaw
James Albert Nelson
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Wyeth LLC
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Description

DESCRIPTION OF THE PRIOR ART A number of compounds structurally related to the compounds of this invention are claimed in prior art.
JP 02306916A claims a class of benzazole compounds of the formula below, where X is
R
R2
X
S or N, which are inhibitors of platelet adhesion for the treatment .of arteriosclerosis, ischemic heart diseases, chronic arterial obstruction, and acute or chronic nephritis. In the above formula, RI includes -(O-A)m-NR 4
R
5 where A is lower alkylene, m is 0 or 1, R 4 and R 5 include hydrogen, phenyl(lower)alkyl, or NR 4
R
5 is a 5-6 membered saturated or unsaturated heterocycle and R 2 includes phenyl optionally substituted by 1-3 substituents selected from optionally halogenated lower alkoxy, lower alkyl, hydroxy, halogen or aminoalkoxy.
15 DE 3830060 claims a class of 2-Arylbenzimidazole erythrocyte aggregation inhibiting compounds of the following formula
R,
R
R
SH C 6 3 where R 4 is methyl, cyano, carboxamido or aminomethyl, R 5 is H or alkyl, R 6 is alkyl or 20 cycloalkyl or R 5 and R 6 completes a cyclohexane ring which are useful for the treatment of circulatory disorders and shock.
Jaen et al, J. Med. Chem., vol 31, no. 8, 1988 pages 1621 to 1625 discloses certain [(arylpiperazinyl)alkoxy]anilines with dopaminergic properties. EP 237 781 discloses certain phenyl and heterocyclic tetrahydropyridyl and piperazinyl alkoxy benzheterocyclic compounds as antipsychotic agents. EP 707 007 discloses certain amino(thio)ether derivatives as CNS active agents. WO 97 23216 discloses 4-substituted piperidine analogs and their use as selective active antagonists of N-methyl-D-aspartate receptors. W098 08817 discloses certain 4-aminoethoxy indoles as dopamin D2 agonists and as 5HTIA ligands.
The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any TR~ the material referred to was published, known or part of the common general kn wledge in Australia as at the priority date of any of the claims.
\X 2 1 SUMMARY OF THE INVENTION Accordingly, the present invention provides compounds of Formula I:
ONR
Y I
HN-
R
1 wherein: RI is hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, straightchain or branched alkyl group having up to 6 carbons or benzyl optionally substituted by one to three substituents selected from halogen, amino, nitro, hydroxy, and CI-C 6 alkoxy; R2 is hydrogen or CI-C 6 alkyl; R3 is hydrogen, straight-chain or branched alkyl group having up to 10 carbon -atoms, cyclohexylmethyl, -(CH 2 )nAr where Ar is phenyl, thienyl, furanyl, or pyridinyl, each optionally substituted by one to two substituents selected from halogen, CI-C 6 alkoxy, trifluoromethyl and Ci-C 6 alkyl and m is 1 to 3; or R 3 is phenylbutyl; or NR 2
R
3 is 1,2,3,4-tetrahydroquinolin-1-yl or 1,2,3,4-tetrahydroisoquinolin-2-yl; Y is hydrogen, halogen, lower alkyl, amino, or lower alkoxy; or the compound of formula I is naphthalen-l-ylmethyl-[2-(2-trifluoromethyl-1H-benzoimidazol-4yloxy]-ethyl]-amine: n is or the compound of formula I is naphthalen-l-ylmethyl-[2-(2-trifluoromethyl-1Hbenzoimidazol-4-yloxy]-ethyl]-amine: provided that when R 1 is aminomethyl and Y is hydrogen, R 2 and R 3 are not both hydrogen; and the pharmaceutically acceptable salts thereof.
The pharmaceutically acceptable acid addition salt having the utility of the free base are prepared by methods well known to the art with both inorganic or organic acids, including but not limited to fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene-sulfonic, hydrochloric hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
The compounds of Formula I, where RI is hydrogen, can be prepared by the overall sequence as follows: Scheme I OH HO O N
N
Y- R Y R N triphenylphosphine N H diethyl azodicarboxylate H 2 n S* ethyl acetate R2 R 2 N-H N R 1. R3 O
N'R
y
R
1 2. HC1 H N HC1 salt methanol- H ethyl acetate The compounds of Formula 1, where Rl is not hydrogen, can be prepared by the overall sequence as follows: Scheme 11
OH
NH
Y-
NO
2 ~CNH 2 NO 2- 2 (n 1 or 2) a a a R 2 N R 3 n 2H 2 NO 2 H 2 NNH 2_ Pd/C or Raney Nickel ethanol R 2 CX NH 2 NH 2 1. R '-CO 2
H
2. HCl NR g.>R1
H
HC1 salt The compounds of Formula I, where R2 is hydrogen, the secondary amine can be protected by a trifluoroacetyl group prepared by the overall sequence as follows: Scheme III
H
NH
2
Y-
NO
2 0 <CF 3 trifluoroacetic anhydride
H
2
NNH
2 P ethanol
S.
S
S* S 55
S.
S
S S S S S 55 5 S S
S
S
S
S
NO
2 O CF3
NH
2
NNH
2 1. R'-CO 2
H
2. K 2 C0 3 methanol 3. HO1
N
N
H HCl salt An intermediate for compounds of Formula I where Y is halogen can be prepared by the following sequence:
NH
2 NO02
NCS
CH
3
CN
NH
2
NO
2 2 (n 1) Specific exemplification of the production of representative compounds of this invention is given in the following procedures: Intermediate 1 4-(2-Chloroethoxy)-benzimidazole To a solution of 4-hydroxybenzimidazole (3.1 g, 32.4 mmol), triphenylphosphine (12.75 g, 48.6 mmol) and 2-chloroethanol (5.2 g, 64.8 mmol) in tetrahydrofuran (75 mL) at 0 5 C was added over 30 min a solution of diethyl azodicarboxylate (8.5 g, 48.7 mmol) in tetrahydrofuran (75 mL). The mixture was warmed to 230 C and stirred for 48 hr. The solvent was removed under vacuum to give a dark brown oil. Purification by chromatography (silica gel, ethyl acetate-1% 2M NH3 in methanol) afforded 2.9 g of a solid residue that was recrystallized from ethyl acetate to give the title compound as a white solid, mp 153-154 C.
Elemental analysis for C9H9C1N20: Calc'd: C, 54.97; H, 4.61; N, 14.25 Found: C, 54.86; H, 4.38; N, 14.26 Intermediate 2a (n=l) 2-(2-Chloro-ethoxy)-6-nitro-phenylamine A slurry containing 2-amino-3-nitrophenol (32.0 g, 0.208 mol), 1,2dichloroethane (260.0 g, 2.65mol), potassium carbonate (35.0 g, 0.252 mol) and 2butanone (750 mL) was refluxed for 24 hr. The mixture was cooled, filtered and the solids were washed with ethyl acetate. The filtrate was concentrated to an oily residue that was dissolved in ethyl acetate (500 mL). The organic layer was washed with 1 N sodium hydroxide (250 mL), water (500 mL), and brine (2X 500 mL), dried over anhydrous magnesium sulfate. Concentration of the filtered solution and trituation of the residue with hexane afforded 37.8 g of product as an orange solid, mp 71-73 °C; S. MS (+)PBEI m/e 216/218 Elemental analysis for C8H9C1N203: Calc'd: C, 44.36; H, 4.19; N, 12.93 Found: C, 44.45; H, 4.02; N, 12.97 Following this general procedure above utilizing 1,3-dibromopropane afforded intermediate 2b, 2-(3-bromo-propoxy)-6-nitro-phenylamine, as a yellow solid, (78.7%) mp 88-89 MS El m/e 274/276 25 Elemental analysis for C9H11BrN203: Calc'd: C, 39.29; H, 4.03; N, 10.18 Found: C, 39.71; H, 3.91; N, 10.27
USL
Intermediate 3a 2-(2-Benzylamino-ethoxy)-6-nitro-phenylamine A mixture of 2-(2-chloroethoxy)-6-nitro-phenylamine (2a, 3.0 g, 13.8 mmol) and benzylamine (9.0 g, 84.0 mmol) was heated at 100-1100 C for 6 hr. The excess benzylamine was removed by distillation under vacuum (70 750 C 0.1 mm Hg (13.3 Pa)) The residue was poured into 1 N sodium hydroxide (300 mL) and extracted with ethyl acetate (2X, 300 mL). The combined organic layer was washed with water (2X, 300 mL) and brine (300 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give 5.1 g of crude red oil.
Purification by chromatography (500 g silica gel, ethyl acetate 2 M NH3 in methanol, 20 1 afforded 3.54 g of a red semi-solid, mp 33-60 MS El m/e 287 Elemental analysis for Cl5H17N303: Calc'd: C, 62.71; H, 5.96; N, 14.62 Found: C, 62.64; H, 6.04; N, 14.23 This general procedure utilizing 4-methyl-benzylamine, thiophene-2-methylamine, 1-naphthalenemethylamine, 1,2,3,4-tetrahydroisoquinoline afforded: 3b 2-[2-(4-Methyl-benzylamino)-ethoxy]-6-nitro-phenylamine as a yellow solid (89.0 mp 55-57 MS El m/e 301 Elemental analysis for C 6H 19N303: Calc'd: 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 as a red semisolid material Elemental analysis for C13HI5N303S: Calc'd: 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 as a yellow solid (76.3 mp 66-67 MS El m/e 337(M+).
SR A 8 AMENDED S-EET WO 98/35945 WO 9835945PCT/1JS98/00613 Elemental analysis for C19H19N303: Calc'd: 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-nitro-phenylamine as a yellow solid (87. mp 95-96 MS El mWe 313 Elemental analysis for C I7H1I9N303: Calc'd: C, 65.16; H, 6.11; N, 13.41 Found: C, 64.87; H, 6.11; N, 13.40 This general procedure utilizing 2-(3-bromo-propoxy)- 6-nitro- phenylarnine (2b, n=2) and benzylamine afforded: 3f 2-(3-Benzylamino-propoxy)-6-nitro-phenylamine as a viscous orange oil (85.5 MS El mWe 301 Elemental analysis for C16H19N3O3: Calc'd: C, 63.77; H, 6.36; N, 13.94 Found: C, 63.66; H, 6.28; N, 13.89 This general procedure utilizing 4-chloro-2- (2-chloro-ethoxy)-6-nitro-phenylamine and benzylamine, 4-chloro-benzylamine afforded: 3.g 2-(2-Benzylamino-ethoxy)-4-chloro-6-nitro-phenylamine as a orange-brown colored solid (54.0 mp 87-88 IC; MS El mWe 32 1/323 Elemental analysis for C1ISH1I6ClN3O03: Calc'd: C, 55.99; H, 5.01; N, 13.06 Found: C, 55.85; H, 4.90; N, 13.13 3h 2-[2-(4-Chloro-benzylaniino)-ethoxyl-4-chloro-6-nitro-phenylamrine as an orangebrown colored solid (83.0 mp 116-118 0
C.
Elemental analysis for C13H15C12N3O2: Calc'd: C, 50.58; H, 4.24; N, 11.80 WO 98/35945 PCT/US98/00613 Found: C, 50.65; H, 4.13; N, 11.51 31 2-[2-(4-Fluoro-benzylamino)-ethoxy]-6-nitro-phenylamine as an orange solid (89.8 mp 72-74 °C.
Elemental analysis for C15H16FN303: Calc'd: C, 59.01; H, 5.28; N, 13.76 Found: C, 58.92; H, 5.16; N, 13.71 to 3j 2-Nitro-6-[2-(4-trifluoromethyl-benzylamino)-ethoxy]-phenylamine as an orange solid (86.7 mp 64-66 OC.
Elemental analysis for C16H16F3N303: Calc'd: 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]-phenylamine quarter hydrate as a viscous orange oil (83.4 MS El m/e 315 (M Elemental analysis for C17H21N303 0.25 Calc'd: 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 To a mixture containing 2-(2-benzylamino-ethoxy)-6-nitro-phenylamine (3a, 0.5 g, 1.74 mmol), 10% palladium on carbon (0.1 g) in ethanol (20 mL) was slowly added a solution of hydrazine hydrate (0.6 mL) in ethanol (6.0 mL). The mixture was heated to oC and stirred at that temperature for 16 hr. The mixture was cooled to 25 OC, filtered and the catalyst was washed with ethanol. The filtrate was concentrated under vacuum and the residue was diluted with ethyl acetate (100 mL). The organic layer was washed with water (2X, 100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give 0.38 g (85.5% crude yield) of product as a brown viscous oil. This material was not purified further, but used immediately in the next step.
-WO 98/35945 WO 9835945PCTIUS98/00613 This general procedure utilizing 2-[2-(4-methyl-benzylamino)-ethoxy]-6-nitrophenylamnine 2-nitro-6- {2-[(thiophen-2-ylmethyl)-amino] -ethoxy)I-phenylamine (3c), 2- (2-I(naphthalen- 1-ylmethyl)-aminol-ethoxy) -6-nitro-phenylamine 2- dihydro- 1H-isoquinolin-2-yl)-ethoxy]-6-nitro-phenylamine (3e, and 2-(3-benzylaminopropoxy)-6-nitro-phenylamine (ff) afforded: 4b (4-Methyl-benzylamino)-ethoxy] -benzene- 1 ,2-diamine as a off-white solid (79.4 mp 77-79 MS El Wle 271 Elemental analysis for CI16H21IN30: Calc'd: 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- I ,2-diamine as an ambercolored oil (70.0 MS El Wle 263 4d 3- (2-[(Naphthalen- 1 -ylmethyl)-amino]-ethoxy I -benzene- 1 ,2-diamine quarterhydrateas a black oil (82.0 MS El Wle 307 Elemental analysis for C 19H21IN30 0.25 Calc'd: C, 73.17; H, 6.95; N, 13.47 Found: C, 73.29; H, 6.86; N, 13.30 4e 3- (3,4-Dihydro- 1 H-isoquinolin-2-yl)-ethoxy] -benzene- 1 ,2-diarnine as a solid (95 mp 76-77 This material was characterized as the dihydrochloride 0.4 H20 salt MS El Wle 283 Elemental analysis for C17H21N30 2 HCl 0.4 Calc'd: C, 56.17; H, 6.60; N, 11.56 Found: C, 56.15; H, 6.68; N, 11.25 4f 3-(3-Benzylaniino-propoxy)-benzene-1,2-diamine as an amber-colored oil; MS El mle 271 Elemental analysis for C16112 1N30 0.3 Calc'd: C, 69.44; H, 7.87; N, 15.18 Found: C, 69.47; H, 7.82; N, 15.30 WO 98/35945 WO 9835945PCTILJS98/00613 This general procedure utilizing 2-12-(4-chloro-benzylamino)-ethoxy] -4-chloro-6nitro-phenylamine Q3h) and Raney nickel in place of 10 Pd/C afforded: 4g 3-[2-(4-chloro-benzylamiino)-ethoxy]-4-chloro-benzene- 1,2-diamine as a light-tan colored solid (75.0 mp 109-110 'C.
Elemental analysis for Ci SHi7C12N30: Calc'd: 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-l1,2-diamine as a white solid (82.4 %,mp 70-7 1 'C.
Elemental analysis for C15H18FN30 0.1H20: Calc'd: 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 as a white solid (87.2 mp 94-95 'C.
Elemental analysis for C16H18F3N30: Calc'd: 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]-bneel2daiea nol(62%;M (+)FAB m/e 286 Intermediate N- (2-Amino-3-nitro- phenyoxy)-ethyll -N-benzyl.2,2,2-trifluoroacetamide To a solution containing 2-(2-benzylamino-ethoxy)-6-nitro-phenylamine 0.50 g, 1.74 mmol), triethylaniine (0.50 mL) and methylene chloride (10 mL) was slowly added trifluoroacetic acid anhydride (0.32 mL, 2.26 mmol). After 2 hr, the reaction mixture was poured into I N sodium hydroxide (50 rnL) and extracted with methylene chloride. The WO 98/35945 PCT/US98/00613 organic layer was washed with water (2X, 50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give a crude yellow residue. Crystallization of this material from ethyl acetate-hexane afforded 0.55 g (81.7 of a yellow solid, mp 134-135 OC; MS El mle 383 Elemental analysis for C17H16F3N304: Calc'd: C, 53.27; H, 4.21; N, 10.96 Found: C, 53.09; H, 4.35; N, 10.93 This general procedure utilizing 2 2 -benzylamino-ethoxy)-4-chloro-6-nitrophenylamine (3g) afforded:
N-[
2 2 -Amino-5-chloro-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoroacetamide as a yellow solid (76.9 mp 106-108 oC; MS (+)FAB m/e 418/420 Elemental analysis for C17H 15CF3N304: Calc'd: 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-trifluoroacetamide To a mixture containing N-[2-(2-amino-3-nitro-phenyoxy)-ethyl]-N-benzyl-2,2,2trifluoro-acetamide (5a, 0.4 g, 1.04 mmol), 10% palladium on carbon (0.1 g) in ethanol mL) was slowly added a solution of hydrazine hydrate (0.6 mL) in ethanol (10.0 mL).
The mixture was heated to 55-60 OC and stirred at that temperature for 1 hr. The mixture was cooled to 25 filtered and the catalyst was washed with ethanol. The filtrate was concentrated under vacuum and the residue was diluted with ethyl acetate (100 mL). The organic layer was washed with water (2X, 100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give 0.32 g (87.5% crude yield) of product as a brown viscous oil; MS (+)FAB m/e 354 -AHP-96118 This general procedure utilizing N-[2-(2-amino-5-chloro-3-nitro-phenoxy)-ethyl]- N-benzyl-2,2,2-trifluoro-acetamide (5b) afforded: 6b N-Benzyl-N-[2-(2,3-diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-acetamide as a brown viscous oil (91.3 MS El m/e 387/389 Elemental analysis for C 17H I 17C1F3N302: Calc'd: 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 A solution of 2-(2-chloro-ethoxy)-6-nitro-phenylamine (2a, 30.0 g, 0.14 mol), Nchlorosuccinamide and acetonitrile (1.3 L) was refluxed for 4 hr. 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 brine (250 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give an orange solid residue. Crystallization from ethyl acetate-hexane gave 33.5g (95.3 as orange solid, mp 109-110 MS El m/e 250/252/254 Elemental analysis for C8H8C12N203: Calc'd: C, 38.27; H, 3.21; N, 11.16 Found: C, 38.15; H, 3.10; N, 10.96 Example 1 [2-(1H-Benzoimidazol-4-yloxy)-ethyl]-benzyl-amine A solution of 4-(2-chloroethoxy)-benzimidazole 0.39g, 1.98mol) and benzylamine (9 mL) was heated at 100-1100 C for 3.5hr. The solvent was concentrated under vacuum (50-60 0 C/0. mmHg (13.3 poured into 1 N sodium hydroxide (50 mL) and extracted with ethyl acetate (2X, 50 mL). The combined organic layer was washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and 14 AMBNiLE4D rET AHP-96118 the solvent removed under vacuum to give 0.58 g of a viscous yellow oil. Purification by chromatography (60 g silica gel, methylene chloride-0.5% 2 M NH3 in methanol) afforded 0.364 g (68.7 of a yellow oil. This material was dissolved in as ethyl acetate-methanol mixture and treated with as excess amount of hydrogen chloride to give the title compound (0.38 g, 58.5 as a white solid, mp 256-259 °C decomposed; MS El m/e 267 Elemental analysis for Ci6HI7N30 2HC1 0.5H20: Calc'd: 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-benzoimidazol-4-yloxy)-ethyl]-amine A solution of 3-(2-benzylamino-ethoxy)-benzene-l,2-diamine (4a, 0.35 g, 1.36 mmol) and acetic acid (10 mL) was refluxed for 14 hr. The solvent was concentrated under vacuum (50 600 C 0. 1 mm Hg (13.3 Pa)) and the residue was dissolved in ethyl acetate mL).
The organic layer was washed with 1 N sodium hydroxide (50 mL), water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give crude base. Purification by chromatography (35 g silica gel, ethyl acetate- 1% 2 M NH3 in methanol) afforded 0.29 g (76.3 of pure base as a tan -colored solid foam. This material was dissolved in as ethyl acetate-methanol mixture and treated with as excess amount of IN hydrogen chloride to give the title compound (0.33 g, 90.0 as a white solid, mp >2500 C; MS El m/e 281 (M Elemental analysis for C17H19N30 2HCl: Calc'd: C, 57.63; H, 5.97; N, 11.61 Found: C, 57.23; H, 5.89; N, 12.86 AMENDED SHEET Example 3 Benzyl-[2-(2-trifluoromethyl-1H-benzoimidazol-4-yloxy)-ethyl]-amine A solution of N-[2-(1,2-diamino-benzene-3-yloxy)-ethyl]-N-benzyl-2,2,2trifluoro-acetamide (6a, 1.0 g, 2.83 mmol) and trifluoroacetic acid (10 mL) was refluxed for 4 hr. The solvent was concentrated under vacuum (50 60" C /0.1 mm Hg (13.3 Pa)) and the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed with 1 N sodium hydroxide (50 mL), water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give a viscous oil residue. Purification by chromatography (140 g silica gel, ethyl acetate-hexane- 2 M NH3 in methanol (10 10 1) afforded 0.86 g (70.7 of N-benzyl-2,2,2-trifluoro- N-[2-(trifluoromethyl-lH-benzoimidazol-4-yloxy)-ethyl]-acetamide as a tan-colored solid foam; MS EI m/e 431 A mixture of N-benzyl-2,2,2-trifluoro-N-[2-(trifluoromethyl- H-benzoimidazol-4yloxy)-ethyl]-acetamide (0.78 g, 1.80 mmol), 6% aqueous methanol (35 mL) and potassium carbonate (1.7 g) was refluxed for 3 hr. The mixture was cooled to 25 °C, poured into water (200 mL) and extracted with ethyl acetate (3X 150 mL). The organic layer was washed with water (200 mL) and brine (200 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give a solid residue.
Crystallization of this material from ethyl acetate afforded 0.50 g (83.5 of benzyl-[2-(2trifluoromethyl-lH-benzoimidazol-4-yloxy)-ethyl]-amine 0.25 ethyl acetate as a white solid, mp 130-131 MS El m/e 335 Elemental analysis for C17HI6F3N30 0.25 C4H802: Calc'd: C, 60.50; H, 5.08; N, 11.76 Found: C, 60.54; H, 4.95; N, 11.72 Benzyl-[2-(2-trifluoromethyl- H-benzoimidazol-4-yloxy)-ethyl]-amine 0.25 ethyl acetate (0.40 g, 2.61 mmol) was dissolved in as ethyl acetate-methanol mixture and treated with as excess amount of IN hydrogen chloride to give the title compound (0.35 g, 79.1 as a white solid, mp 194-195 MS El m/e 335 Elemental analysis for C17H19N30 HCI: Calc'd: C, 57.63; H, 5.97; N, 11.61 Found: C, 57.23; H, 5.89; N, 12.86 WO 98/35945 PCTIUS98/00613- Example 4 (4-Met hyl- benzyl)- (2-t ri f Iuoromet hyl -1H -benzoi midazol -4 -yloxy)ethyl]-amine T'he general procedures used in example 2 utilizing 3-[2-(4-methyl-benzylaniino)ethoxy]-benzene- 1,2-diamine (4b) and trifluoroacetic acid afforded: (4-Methyl-benzyl)-112-(2-trifluoromethyl- 1H-benzoimidazol-4-yloxy)-ethyl]-amine 0.25 ethyl acetate as a white solid (60.5 %,mp 154-158 MS El mWe 349 Elemental analysis for C1I8H 18F3N30 0.25 C4H802: Calc'd: 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-benzoimiidazol-4-yloxy)-ethyl]amine dihydrochioride as a white solid (90.1 mp 230-233 TC; MS El Wle 349 Elemental analysis for Ci 8111 8F3N30 2HCl: Calc'd: C, 51.20; H, 4.77; N, 9.95 Found: C, 50.92; H, 4.69; N, 9.89 Example (2-Ben zyl- 1H- bcnzoimidazol -4-yloxy)- ethyl] (4-methyl-benzyl)-amine T'he general procedures used in example 2~ utilizing 3-[2-(4-methyl-benzylamino)ethoxy] -benzene- 1,2-diamine (4b) and phenylacetic acid afforded: [2-(2-Benzyl- 1H-benzoimidazol-4-yloxy)-ethyl]-(4-methyl-benzyl)-amine dihydrochloride as a white solid (65.8 mp >250 TC; MS EI mWe 371 Elemental analysis for C24-125N30 2HCl: Calc'd: C, 64.86; H, 6.12; N, 9.46 Found: C, 64.43; H, 6.15; N, 9.31 WO 98/35945 WO 9835945PCTIUS98/00613 Example 6 (4-Methyl-benzyl)-{2- pentafl uoro-ethyl)- 111- benzoimi dazol- 4-yloxy]-ethyl} -amine The general procedures used in example 2 utilizing 3-12-(4-methyl-benzylamino)ethoxy] -benzene-1,2-diamine (4b) and pentafluoropropionic acid afforded: (4-Methyl-benzyl)- 1,1 ,2,2,2-pentafluoro-ethyl)- 1H-benzoimidazol-4yloxy] -ethyl)}-amine 1.25 hydrate as a white solid (75.3 mp 85-90 TC decomposed; MS EI We 399 Elemental analysis for Cl9HI1FSN3O*- 1.25 Calc'd: C, 54.09; H, 4.90; N, 9.96 Found: C, 53.83; H, 4.65; N, 9.76 (4-Methyl-benzyl)- 1,1 ,2,2,2-pentafluoro-ethyl)- 1 H-benzoimidazol-4yloxy] -ethyl I1-amine hydrochloride as a white solid (79.7 mp 180 TC decomposed; MS El mWe 399 Elemental analysis for C I9H17F5N30' HCl: Calc'd: C, 52.36; H, 4.39; N, 9.64 Found: C, 52.23; H, 4.31; N, 9.54 Example 7 Thiophen-2-ylmethyl- [2-(2-trifluoromethyl- 1H -benzoimnidazol-4-yloxy)ethyl]-amine The general procedures used in example 2 utilizing 3-{2-[(thiophen-2-ylmethyl)amino]-ethoxy I -benzene- 1,2-diamine and trifluoroacetic acid afforded: Thiophen-2-ylmethyl-12-(2-trifluoromethyl- 1H-benzoimnidazol-4-yloxy)-ethyl]amine 1.6 Hydrochloride as a tan solid (58.3 mp 184 MIS El mWe 341 Elemental analysis for C I 8H 1 8F3N30 1 .6HCl: WO 98/35945 WO 9835945PCT/US98/00613 Calc'd: C, 44.98; H, 4.04; N, 10.38 Found: C, 44.99; H, 4.05; N, 10.33 Example 8 Benzy]-[3-(2-trifluoromethyl-1IH- benzoimnidazol-4-yloxy)- propyl I-amnine The general procedures used in example 2 utilizing 3-(3-benzylamino-propoxy)benzene- 1,2-dianiine (4D~f and trifluoroacetic acid afforded: Benzyl-[3-(2-trifluoromethyl- 1 H-benzoimidazol-4-yloxy)-propyl] -amine hemi hydrate as a tan solid foam (57.6 mp 50-70 MS El Wle 349 Elemental analysis for C1I8H I8F3N30 0.5 Calc'd: C, 60.33; H, 5.34; N, 11.73 Found: C, 60.34; H, 5.30; N, 11.84 Benzyl- [3-(2-trifluoromethyl- I H- ben zoimidazol-4-yloxy)-propyl] -amine Dihydrochioride as a white solid (98.0 mp 194-197 MS El mWe 349 Elemental analysis for C1I8H 18F3N30 2 HCl: Calc'd: C, 51.20; H, 4.77; N, 9.95 Found: C, 51.09; H, 4.49; N, 9.86 Example 9 B enzyI-{1 2 pen taf Iuo ro-eth yl) 1 -ben zoii da zol yl oxy.
ethyl}-amnine The general procedures used in example 3 utilizing N- [2-(1,2-diamino- benzene- 3yloxy)-ethyll-N-benzyl-2,2,2-trifluoro-acetamide (6a' and pentafluoropropionic acid afforded: Benzyl- 2- 1,1 ,2,2,2-pentafluoro-ethyl)- 1 H-benzoimidazol-4-yloxyl -ethyl)} amine as a white solid (59.8 mp 152-153 MS El mWe 385 WO 98/35945 PCT/US98/00613- Elemental analysis for C1 8H1 6F5N30: Calc'd: C, 56.11; H, 4.19; N, 10.91 Found: C, 56.02; H, 4.10; N, 10.73 Benzyl- ,1 ,2,2,2-pentafluoro-ethyl)- 1H-benzoimidazol-4-yloxy]-ethyl)}amine hydrochloride 0.75 hydrate as a white solid (69.4 mp 120-135 0 C; MS (+)ESI mle 386 Elemental analysis for C18H16F5N30 HCI 0.75 Calc'd: C, 49.67; H, 4.28; N, 9.65 Found: C, 49.88; H, 3.95; N, 9.66 Example Naphthalen-1I-ylmethyl- (2-t rifluoromethyl-11I--benzoimidazol-4-yloxy]ethyl]-andne The general procedures used in example 2 utilizing 3-{[2-[(naphthalen-1I-ylmethyl)amino]-ethoxy) -benzene- 1 ,2-diamine (Ad) and trifluoroacetic acid afforded: Naphthalen- 1 -ylmethyl- [2-(2-trifluoromethyl- 1H-benzoimidazol-4-yloxy]-ethyl I amine as a white solid (63.1 mp 130-133 0 C; MS El 385 mWe Elemental analysis for C21IH1I8F3N30:.
Calc'd: C, 65.45; H, 4.7 1; N, 10.90 Found: C, 65.28; H, 4.43; N, 10.57 Naphthalen- 1 -ylmethyl- [2-(2-trifl uoromethyl- 1H-benzoimidazol-4-yloxy] -ethyl] amine hydrochloride as a white solid (94.8 mp 208-209 MS El mle 385 Elemental analysis for C1 8H I 8F3N30 -HCl: Calc'd: C, 59.79; H, 4.54; N, 9.96 Found: C, 59.39; H, 4.45; N, 9.81 .WO 98/35945 WO 9835945PCT/US98/00613 Example 11 T hiophen -2-ylmethyl (1 H-benzoimi dazol -4-yloxy)-ethyl]-ami ne The general procedures used in example 2 utilizing 3-{2-[thiophen-2-ylmethyl)amino] -ethoxy) -benzene-l1,2-diamine and formic acid afforded: Thiophen-2-ylmethyl-[2..( H-benzoimidazol-4-yloxy)-ethyl]-amine quarter hydrate as a viscous yellow oil (63.2 MS El Wle 273 Elemental analysis for C I4H1I5N30S 0.25 Calc'd: C, 60.52; H, 5.62; N, 15.12 Found: C, 60.85; H, 5.49; N, 15.39 Thiophen-2-ylmethyl-[2-(lIH-benzoimidazol-4-yloxy)-ethyl]-wmine dihydrochloride hemihydrate as a white solid (69.2 mp 248-252 'C decomposed; MS El mle 273 Elemental analysis for C14H15N3OS 2.0 HCl 0.5 Calc'd: 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)-1Hbenzoimidazol -4-yloxyl -ethyl}I-amine The general procedures used in example 2 utilizing 3-[2-(4-methyl-benzylamino)ethoxy] -benzene-1,2-diamine (4b) and heptafluorobutyric acid afforded: (4-Methyl-benzyl)- 1,1 ,2,2,3,3,3-heptafluoro-propyl)- 1H-benzoimidazol-4yloxy] -ethyl) -amine as a white solid (63.7 mp 144-146 MS El mie 449 Elemental analysis for C20H1I8F7N30: Calc'd: C, 53.46; H, 4.04; N, 9.35 Found: C, 53.23; H, 3.69; N, 9.11 WO 98/35945 WO 9835945PCT/US98/00613 (4-Methyl-benzyl)- 1,1,2,2,3,3 ,3-heptafluoro-propyl)- 1H-benzoimidazol-4yloxy]-ethyl)-amine 1.5 hydrochloride as a white solid (87.6 mp 198-199.5 MS El mWe 449 Elemental analysis for C1I9H I8F5N30 1.5 HCl: Calc'd: C, 47.66; H, 3.90; N, 8.34 Found: C, 47.47; H, 3.76; N, 8.24 Example 13 2- [2-(2-Tritluoromethyl- 1H -benzoimidazol.4-yloxy-ethyl].. 1,2,3,4tetra hydro-isoquinoline The genera] procedures used in example 2 utilizing 3-[2-(3,4-dihydro- 1Hi soq uinolin-2-yl)-ethoxy] -ben zene- 1,2-diamine (ke) and trifouoroacetic acid afforded: 2-12- (2-Trifluoromethyl- 1 H- benzoi midazol-4-yloxy) -ethyl] 1,2,3 ,4-tetrahydroisoquinoline quarter hydrate as a white solid (95.8 mp 168-171 0 Q MS El mWe 361 Elemental analysis for C19Hl8F3N30 -0.25 Calc'd: C, 62.37; H, 5. 10; N, 11.49 Found: C, 62.52; H, 4.85; N, 11.50 2-12-(2-Trifluoromethyl- 1H-benzoimidazol-4-yloxy)-ethyl] -1,2,3 ,4-tetrahydroisoquinoline dihydrochloride as a white solid (94.3 mp 210-214 TC decomposed; MS El mWe 361 Elemental analysis for C1I9H1I8F3N30 2 HCl: Calc'd: C, 52.55; H, 4.64; N, 9.68 Found: C, 52.20; H, 4.8 1; N, 9.33 WO 98/35945 WO 9835945PCT/US98OO613 Example 14 Benzyl-[2-(6-chloro-2-trifluoromethyl- 1H-benzoimidazol-4-yloxy)-ethyla mine The general procedures used in example 3 utilizing N-benzyl-N-[2-(2,3-diamino-5chloro-phenoxy)-ethyl]-2,2,2-trifluoro-acetamide and trifluoroacetic acid afforded: Benzyl-[2-(6-chloro-2-trifluoromethyl- 1H-benzoimidazol-4-yloxy)-ethyl-amine as a white solid (76.4 mp, 17 1-172 MS El Wie 369 (Mt).
Elemental analysis for C17Hl5C1F3N30: Calc'd: 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-benzoimidazol-4-yloxy)-ethyl-amine as a white solid (73.4 mp 210-2 12 TC; MS El mWe 369 Elemental analysis for C17H15CIF3N3O HC1: Calc'd: C, 50.26; H, 3.97; N, 10.34 Found: C, 50.29; H, 3.81; N, 10.32 Example 4-Chloro-benzyl-[2-(6-chloro..2-trifluoromethyl-1H-benzoimidazol-4yloxy)-ethyl-amine The general procedures used in example 2 utilizing 3-[2-(4-chloro-benzylamino)ethoxy]-4-chloro-benzene-1,2-diamiine (4g) and trifluoroacetic acid afforded: 4-Chloro-benzyl-[2-(6-chloro-2-trifluoromethyl- 1H-benzoimidazol-4-yloxy)-ethylamine fumnatate, as a light-gray colored solid (79.6 np 191-193 TC; MS El mie 403/405/407 Elemental analysis for C17H14C13F3N3O.- C4H404: Calc'd: C, 48.48; H, 3.49; N, 8.08 Found: C, 48.17; H, 3.26; N, 8.11 WO 98/35945 WO 983545PCT/US98/00613 Example 16 (4-Fluoro-benzyl)-2 [2-(2-trifluoromethyl- 1H-benzoimidazol-4-yloxy)ethyl]-amine The general procedures used in example 2 utilizing 3-[2-(4-fluoro-benzylamino)ethoxy] -benzene- 1,2-diamine (4h) and trifluoroacetic acid afforded: (4-Fluoro-benzyl)-21j2-(2-trifluoromethyl- 1H-benzoimidazol-4-yloxy)-ethyl]-amine hydrochloride hemnihydrate as a white solid (50.4 mp 225-227 0 Q MS El mie 353(M+).
Elemental analysis for C17H1SF4N3O0l .0 HCI'0.5 Calc'd: 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-benzoimidazol-4-yloxy)-ethyl]-(4t rifl uoromet hy I- ben zyl )-amine The general procedures used in example 2 utilizing 3-12-(4-trifluoromethylbenzylamiino)-ethoxy] -benzene- 1,2-diamine (4i) and trifluoroacetic acid afforded: [2-(2-Trifluoromethyl- 1H-benzoimidazol-4-yloxy)-ethyl]-(4-trifluoromethylbenzyl)-aniine hydrochloride as a white solid (80.5 mp 188-190 MS (+)FAB mie 404 Elemental analysis for C I8H 15F6N30* 1.0 HCl: Calc'd: C, 49.16; H, 3.67; N, 9.55 Found: C, 49.21; H, 3.50; N, 9.46 WO 98/35945 PCT/US98/00613 Example 18 (3-Phenyl-propyl)-[2-(2-trifluoromethyl-lH-benzoimidazol-4-yloxy)ethyl]-amine The general procedures used in example 2 utilizing 3-[2-(3-phenyl-propylamino)ethoxy]-benzene-1,2-diamine (4j) and trifluoroacetic acid afforded: (3-Phenyl-propyl)-[2-(2-trifluoromethyl-1H-benzoimidazol-4-yloxy)-ethyl]-amine hydrochloride as a white solid (88.7 mp 167-170 OC; MS (+)FAB m/e 364 Elemental analysis for C19H20F3N30 1.0 HCI: Calc'd: C, 57.07; H, 5.29; N, 10.51 Found: C, 56.89; H, 5.15; N, 10.28
PHARMACOLOGY
The compounds of this invention are dopamine autoreceptor agonists, that is, they serve to modulate the synthesis and release of the neurotransmitter dopamine. They are thus useful for treatment of disorders of the dopaminergic system, such as schizophrenia, Parkinson's disease and Tourette's syndrome. Such agents are partial agonists at the postsynaptic dopamine D2 receptor and are thereby useful in the treatment of alcohol and drug addiction.
Affinity for the dopamine autoreceptor was established by a modification of the standard experimental test procedure of Seemen and Schaus, European Journal of Pharmacology 203: 105-109, 1991, wherein homogenized rat striatal brain tissue is incubated with 3 H-quinpirole (Quin.) and various concentrations of test compound, filtered and washed and counted in a Betaplate scintillation counter.
High affinity for the dopamine D-2 receptor was established by the standard experimental test procedure of Fields, et al., Brain Res., 136, 578 (1977) and Yamamura et al., eds., Neurotransmitter Receptor Binding, Raven Press, N.Y. (1978) wherein homogenized limbic brain tissue is incubated with 3 H-spiroperidol (Spiper.) and various concentrations of test compound, filtered and washed and shaken with Hydrofluor scintillation cocktail (National Diagnostics) and counted in a Packard 460 CD scintillation counter.
WO 98/35945 PCT/US98/00613 The results of the tests with compounds representative of this invention are given in the immediately following table.
Example No. IC50 (nM) IC50 (nM) Ratio D2 Quin. D2 Spiper 1 26.75 2 8.85 339 38.3 3 0.36 23.7 65.8 4 0.74 29.9 40.4 54.8 2159 39.4 6 1.44 66.5 46.2 7 1.03 37.35 36.3 8 86.76 1456 16.8 9 1.41 41.88 29.7 0.86 81.5 94.8 11 52.8 12 5.12 118.0 23.0 13 8.00 314.4 39.4 14 1.42 150.5 106 7.77 395.0 50.8 16 0.74 49.0 66.2 17 1.16 87.0 75.0 18 0.56 Hence, the compounds of this invention effect the synthesis of the neurotransmitter dopamine and thus are useful in the treatment of dopaminergic disorders such as schizophrenia, Parkinson's disease, Tourette's Syndrome, alcohol addiction, cocaine addiction, and addiction to analagous drugs.
Applicable solid carriers for pharmaceutical compositions containing the compounds of this invention can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintergrating agents or an encapsulating material. In 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 shape and size desired. 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, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of.this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g.
15 cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils fractionated coconut oil and arachis 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 sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can I: be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection.
Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
S* Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled 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 any such compositions in package form.
The dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician. The variables involved include the specific psychosis and the size, age and response pattern of the patient.
Throughout the description and claims of the specification the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps.

Claims (1)

  1. WHAT IS CLAIMED IS:
    ( 1 ) A compounds of formula I :
    wherein:
    R1 is hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, straight- chain or branched alkyl group having up to 6 carbons or benzyl optionally substituted by one to three substituents selected from halogen, amino, nitro, hydroxy, Cι-C6 alkoxy; R2 is hydrogen or Cι-C6 alkyl.
    R3 is hydrogen, straight-chain or branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl, -(CH2)mAr where Ar is phenyl, thienyl, furanyl, or pyridinyl, each optionally substituted by one to two substituents selected from halogen, -C6 alkoxy, trifluoromethyl or Cι-C6 alkyl; or NR2R3 is 1,2,3,4-tetrahydroquinolin-l-yl or l,2,3,4-tetrahydroisoquinolin-2- yi; Y = halogen, lower alkyl, amino, and lower alkoxy; n = l-5; or a pharmaceutically acceptable salt thereof.
    (2) A compound according to claim 1 wherein R2 is benzyl, substituted benzyl, thienylmethyl, tetrahydroisoquinoline, furanylmethyl, phenybutyl, cyclohexylmethyl, or 4- fluorobutyrophenone and Rl is trifluoromethyl or tetrafluoroethyl.
    (3) A compound according to claim 1 which is [2-(lH-benzoimidazol-4-yloxy)-ethyl]- benzyl-amine or a pharmaceutically acceptable salt thereof.
    (4) A compound according to claim 1 which is benzyl-[2-(2-methyl-lH-benzoimidazol- 4-yloxy)-ethyl]-amine or a pharmaceutically acceptable salt thereof. (5) A compound according to claim 1 which is benzyl-[2-(2-frifluoromethyl-lH- benzoimidazol-4-yloxy)-ethyl]-amine or a pharmaceutically acceptable salt thereof. (6) A compound according to claim 1 which is (4-methyl-benzyl)-[2-(2- trifluoromethyl-lH-benzoimidazol-4-yloxy)-ethyl]-amine or a pharmaceutically acceptable salt thereof.
    (7) A compound according to claim 1 which is [2-(2-benzyl-lH-benzoimidazol-4- 5 yloxy)-ethyl]- (4-methyl-benzyl)-amine or a pharmaceutically acceptable salt thereof.
    (8) A compound according to claim 1 which is (4-methyl-benzyl)-{2-[2-(l,l,2,2,2- pentafluoro-ethyl)-lH-benzoimidazol-4-yloxy] -ethyl} -amine or a pharmaceutically acceptable salt thereof.
    (9) A compound according to claim 1 which is thiophen-2-ylmethyl-[2-(2- l o trifluoromethyl- lH-benzoimidazol-4-yloxy)-ethyl]-amine or a pharmaceutically acceptable salt thereof.
    (10) A compound according to claim 1 which is benzyl-[3-(2-trifluoromethyl-lH- benzoimidazol-4-yloxy)-propyl]-amine or a pharmaceutically acceptable salt thereof.
    (11) A compound according to claim 1 which is benzyl- { 2-[2-( 1 , 1 ,2,2,2-pentafluoro- 15 ethyl)- lH-benzoimidazol-4-yloxy]-ethyl} -amine or a pharmaceutically acceptable salt thereof.
    (12) A compound according to claim 1 which is nNaphthalen-l-ylmethyl-[2-(2- trifluoromethyl-lH-benzoimidazol-4-yloxy]-ethyl]-amine or a pharmaceutically acceptable salt thereof.
    20 (13) A compound according to claim 1 which is thiophen-2-ylmethyl-[2-(lH- benzoimidazol-4-yloxy)-ethyl] -amine or a pharmaceutically acceptable salt thereof. (14) A compound according to claim 1 which is (4-methyl-benzyl)-{2-[2- (1,1 ,2,2,3,3,3-heptafluoro-propyl)- lH-benzoimidazol-4-yloxy]-ethyl } -amine or a pharmaceutically acceptable salt thereof.
    25 (15) A compound according to claim 1 which is 2-[2-(2-trifluoromethyl-lH- benzoimidazol-4-yloxy-ethyl]-l,2,3,4-tetrahydro-isoquinoline or a pharmaceutically acceptable salt thereof.
    (16) A compound according to claim 1 which is benzyl- [2- (6-chloro-2- trifluoromethyl- lH-benzoimidazol-4-yloxy)-ethyl-amine or a pharmaceutically acceptable salt thereof.
    30 (17) A compound according to claim 1 which is 4-chloro-benzyl-[2-(6-chloro-2- trifluoromethyl-lH-benzoimidazol-4-yloxy)-ethyl-amine or a pharmaceutically acceptable salt thereof.
    (18) A compound according to claim 1 which is (4-fluoro-benzyl)-2[2-(2- trifluoromethyl-lH-benzoimidazol-4-yloxy)-ethyl] -amine or a pharmaceutically acceptable
    35 salt thereof. (19) A compound according to claim 1 which is [2-(2-trifluoromethyl-lH- benzoirnidazol-4-yloxy)-ethyl]-(4-trifluoromethyl-benzyl)-amine or a pharmaceutically acceptable salt thereof.
    (20) A compound according to claim 1 which is (3-phenyl-propyl)-[2-(2- trifluoromethyl-lH-benzoimidazol-4-yloxy)-ethyl] -amine or a pharmaceutically acceptable salt thereof.
    (21) A method of treating diseases in a mammal which respond to treatment with dopamine D2 agonists which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of the formula
    wherein:
    R1 is hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, straight- chain or branched alkyl group having up to 6 carbons or benzyl optionally substituted by one to three substituents selected from halogen, amino, nitro, hydroxy, Cι-C6 alkoxy and Cι-C6 alkyl; R2 is hydrogen or Cι-C6 alkyl.
    R3 is hydrogen, straight-chain or branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl, -(CH2)mAr where Ar is phenyl, thienyl, furanyl, or pyridinyl, each optionally substituted by one to two substituents selected from halogen, Cι-C6 alkoxy, trifluoromethyl or Cι-C6 alkyl; or NR2R3 is 1,2,3,4-tetrahydroquinolin-l-yl or l,2,3,4-tetrahydroisoquinolin-2- yi; Y = halogen, lower alkyl, amino, and lower alkoxy; n = 1-5; or a pharmaceutically acceptable salt thereof.
    (22) The method of treatment according to claim 21 wherein the disease treated is schizophrenia.
    (23) The method of treatment according to claim 21 wherein the disease treated is Parkinson's disease. (24) The method of treatment according to claim 21 wherein the disease treated is Tourette's syndrome.
    (25) The method of treatment according to claim 21 wherein the disease treated is drug or alcohol addiction.
    (26) A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the formula
    wherein:
    R1 is hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, straight- chain or branched alkyl group having up to 6 carbons or benzyl optionally substituted by one to three substituents selected from halogen, amino, nitro, hydroxy, Cι-C6 alkoxy; R2 is hydrogen or Cι-C6 alkyl.
    R3 is hydrogen, straight-chain or branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl, -(CH2)mAr where Ar is phenyl, thienyl, furanyl, or pyridinyl, each optionally substituted by one to two substituents selected from halogen, Cι-C6 alkoxy, trifluoromethyl or -C6 alkyl; or NR2R3 is 1,2,3,4-tetrahydroquinolin-l-yl or l,2,3,4-tetrahydroisoquinolin-2- yi; Y = halogen, lower alkyl, amino, and lower alkoxy; n = 1-5; or a pharmaceutically acceptable salt thereof.
AU59153/98A 1997-02-18 1998-01-13 4-aminoalkoxy-1H-benzimidazole derivatives, their preparation and their use as dopamine autoreceptor (D2) agonists Ceased AU746717B2 (en)

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