CA2278700A1

CA2278700A1 - 4-aminoalkoxy-1h-benzimidazole derivatives, their preparation and their use as dopamine autoreceptor (d2) agonists

Info

Publication number: CA2278700A1
Application number: CA002278700A
Authority: CA
Inventors: Richard Eric Mewshaw; James Albert Nelson
Original assignee: Individual
Current assignee: Wyeth LLC
Priority date: 1997-02-18
Filing date: 1998-01-13
Publication date: 1998-08-20
Also published as: NZ336969A; AU5915398A; BR9807701A; WO1998035945A1; AR011136A1; JP2001509814A; KR20000071129A; ZA981309B; HUP0001302A2; HUP0001302A3; EP0973749A1; AU746717B2; CN1252793A; TW513415B; IL131158A0

Abstract

This invention relates to D2 dopaminergic compounds of formula (I), wherein R1 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, C1-C6 alkoxy; R2 is hydrogen or C1-C6 alkyl. R3 is hydrogen, straightchain 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, C1-C6 alkoxy, trifluoromethyl or C1-C6 alkyl; or NR2R3 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 = 1-5; or a pharmaceutically acceptable salt thereof. These D2 dopaminergic compounds are useful in the treatment of schizophrenia, Parkinson's disease, Tourette's syndrome, and drug or alcohol addiction.

Description

4-AMINOALKOXY-1H-BENZO~AZOLE DERIVATIVES) THEIR PREPARATION
AND THEIR USE AS DOPAMINE AUTORECEPTOR (D2) AGONISTS
FIELD OF INVENTION
This invention relates to 4-(aminoalkoxy)-1H-benzoimidazoles which have dopamine D2 agonist activity and thus are useful in the treatment of schizophrenia, Parkinson's disease, Tourette's syndrome and drug or alcohol addiction, pharmaceutical compositions containing said compounds and processes for the production thereof.
BACKGROUND OF INVENTION
Efforts to induce antipsychotic activity with dopamine autoreceptor agonists have been successful (Dorsini I Adv. Biochem. Psychopharmacol., 16, 645-648, 1977;
Tamminga et al., Science , 200, 567-568, 1975; and Tamminga et al., Archives of General Psychiatry 43(4): 398-402) 1986). A method for determining intrinsic activity at the dopamine D2 receptor was recently reported (Lahti et al.) Mol. Pharm., 42, 432-438, 1993) Intrinsic activity is predicted using the ratio of the "low-affinity agonist" (LowAg) state of the receptor and the "high-affinity agonist" (HighAg) state of the receptor, i.e.
LowAg/HighAg. These ratios correlate with the agonist, partial agonist, and antagonist activities of a given compound, which activities characterize a compounds ability to elicit an antipsychotic effect.
In accordance with this invention, there is provided a group of compounds which are useful antipsychotic agents. The compounds of this invention are dopamine agonists various degrees of intrinsic activity some of which are selective autoreceptor agonists, and therefore partial agonist (i.e. activate only autoreceptors versus postsynaptic D2 dopamine receptors). As such, they provide functional modulation of the dopamine systems of the brain without the excessive blockade of the postsynaptic dopamine receptors which have been observed to be responsible for the serious side effects frequently exhibited by agents found otherwise clinically effective for the treatment of schizophrenia.
Activation of the dopamine autoreceptors results in reduced neuronal firing a well as inhibition of dopamine synthesis and release and therefore provide a means of controlling hyperactivity of the dopaminergic systems. The compounds of this invention were also found to have high intrinsic activity and therefore they can behave as the natural neurotransmitter i.e. as full agonists. As such, they are useful in the treatment of diseases having abnormal concentrations of dopamine could be used as dopamine surrogates possibly in the treatment of Parkinson's disease. The compounds of this invention are essentially free from extrapyramidal side effects (EPS).
~AMEP~ED S~!~ET

. AHP-461 18 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 N
~R 1~
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, R i includes -(O-A)m-NR4R5 where A is lower alkylene, m is 0 or 1, R4 and RS include hydrogen) phenyl(lower)alkyl, or NR4R5 is a 5-6 membered saturated or unsaturated heterocycle and R2 includes phenyl optionally substituted by 1-3 substituents selected from optionally halogenated lower alkoxy, lower alkyl, hydroxy, halogen or aminoalkoxy.
DE 3830060 claims a class of 2-Arylbenzimidazole erythrocyte aggregation inhibiting compounds of the following formula r~. N Ra N
Rs where R4 is methyl, cyano, carboxamido or aminomethyl) RS is H or alkyl, R6 is alkyl or cycloalkyl or RS and R6 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 23?

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 SHTiA ligands.

i~NlEl~~n ~'ET

SUMMARY OF THE INVENTION
Accordingly, the present invention provides compounds of Formula I:
~R3 / R
HN ~N I

wherein:
R1 is hydrogen, 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) vitro, hydroxy, and C i-C6 alkoxy;
R2 is hydrogen or C 1-C6 alkyl;
R3 is hydrogen, straight-chain or branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl, -(CHZ)mAr where Ar is phenyl, thienyl, furanyl, or pyridinyl, each optionally substituted by one to two substituents selected from halogen, Ci-C6 alkoxy, trifluoromethyl and Ci-C6 alkyl and m is 1 to 3;
or NRZR3 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;
n is 1-5;
provided that when Rl is aminomethyl) R~ and R3 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, malefic, 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 III, where R~ is hydrogen, can be prepared by the overall sequence as follows:

~i~.3L .~ ~ 'T

' WO 98/35945 PCTIUS98/00613 -Scheme I
CI
OH Hp O
~~C I
n I ~ I
N triphenylphosphine ~ N
H diethyl azodicarboxylate H
THF

N-H p~N~Rs -M

1, R
s N

DMSO

~ HCl salt HCl H

.
methanol-ethyl acetate The compounds of Formula III, where R 1 is not hydrogen, can be prepared by the s overall sequence as follows:
Scheme II

CI
OH O n N

NH2 / NH2 O~" R H NNH
z 2 N02 N02 ~ 10% Pd/C
NO or 2 In = 1 or 21 2 Raney Nickel ethanol I
O~N~R3 O~'N~Rs NH2 1. R1-C02H N
yR, NH2 2. HCI H HC1 salt io The compounds of Formula III, where R2 is hydrogen, the secondary amine can be protected by a trifluoroacetyl group prepared by the overall sequence as follows:
Scheme III

~ ~N
O~ ~ R3 N~
/~ 3 NH trifluoroacetic O~ R H2NNH2 anhydride / NH2 N 02 ' ethanol ' N02 L
O~~N~R3 O~n~R3 NH2 I. R1-C02H / N
~~Rt NH2 2. m t~ nol ' N
H HCl salt ft 3. HCl An intermediate for compounds of Formula III where Y is halogen can be prepared s by the following sequence:
O~cl o~m n n 'N02 CI ~~N02 2 (n ~ 1 ) Z
1 o Specific exemplification of the production of representative compounds of this invention is given in the following procedures:
Intermediate 1 is 4-(2-Chloroethoxy)-benzimidazole To a solution of 4-hydroxybenzimidazole (3.1 g, 32.4 mmol), triphenylphosphine ( 12.7s g, 48.6 mmol) and 2-chloroethanol (5.2 g, 64.8 mmol) in tetrahydrofuran (75 mL) 2o 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 23° 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 ( 63.8 °lo ) of a solid residue that was recrystallized from ethyl acetate to give the title compound as a 2s white solid, mp 153-154 °C.

WO 98!35945 PCT/US98/00613 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 s Intermediate 2a (n=1) 2-(2-Chloro-ethoxy)-6-vitro-phenyfarnine 1 o A slurry containing 2-amino-3-nitrophenol (32.0 g, 0.208 mol), I,2-dichloroethane (260.0 g, 2.65mo1), potassium carbonate (35.0 g, 0.252 mol) and 2-butanone (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 (S00 mL). The organic layer was washed with 1 N sodium hydroxide (250 mL), ~5 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 (84.6%) of product as an orange solid, mp 71-73 °C; MS (+)PBEI
mle 216/218 (M+).
2o 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 2s Following this general procedure above utilizing 1,3-dibromopropane afforded intermediate 2b, 2-(3-bromo-propoxy)-6-vitro-phenylamine, as a yellow solid, (78.7%) mp 88-89 °C; MS EI mle 274/276 [M+].
Elemental analysis for C9H 11 BrN203:
so Calc'd: 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-vitro-phenylamine A mixture of 2-(2-chloroethoxy)-6-vitro-phenylamine (2a, 3.0 g, 13.8 mmol) and benzylamine (9.0 g, 84.0 mmol) was heated at 100-110° C for 6 hr. The excess benzylamine was removed by distillation under vacuum (70 - 75° 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 (89.3%) of a red semi-solid, mp 33-60 °C; MS EI mle 287 (M+).
Elemental analysis for C 15H 17N3~3~
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-vitro-phenylamine as a yellow solid (89.0 %): mp 55-57 °C; MS EI m/e 301 (M+).
Elemental analysis for C 16H 19N3~3:
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 semi-solid material (88.5%).
Elemental analysis for C 13H I SN3~3S
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-vitro-phenylamine as a yellow solid (76.3 %), mp 66-67 °C; MS EI mle 337(M+).

AMEf~FD D~'~FT

Elemental analysis for C1gH19N303:
Calc'd: C, 67.64; H, 5.68; N, 12.45 Found: C, 67.20; H, 5.66; N, 12.26 s 3e 2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethoxy]-6-vitro-phenylamine as a yellow solid (87.1%), mp 95-96 °C; MS EI mle 313 (M+).
Elemental analysis for C17H19N303:
Zo 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-phenylamine (2b, n=2) and benzylamine afforded:
is 3f 2-(3-Benzylamino-propoxy)-6-vitro-phenylamine as a viscous orange oil (85.5 %);
MS EI mle 301 (M').
Elemental analysis for C1(~I-I19N3~3:
2o 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-vitro-phenylamine L) and benzylamine, 4-chloro-benzylamine afforded:
~g 2-(2-Benzylamino-ethoxy)-4-chloro-6-vitro-phenylamine as a orange-brown colored solid (54.0 %)) mp 87-88 °C; %); MS EI mle 321/323 (M+).
Elemental analysis for C15H16C1N303:
3o Calc'd: C, 55.99; H, 5.01; N, 13.06 Found: C, 55.85; H, 4.90; N, 13.13 2-[2-(4-Chloro-benzylamino)-ethoxy]-4-chloro-6-vitro-phenylamine as an orange-brown colored solid (83.0 %), mp 116-118 °C.
3s Elemental analysis for C 13H 15C12N302:
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 2-[2-(4-Fluoro-benzylamino)-ethoxy]-6-nitro-phenylamine as an orange solid (89.8 %), mp 72-74 °C.
s Elemental analysis for C15H16FN3~3:
Calc'd: C) 59.01; H, 5.28; N) 13.76 Found: C, 58.92; H, 5.16; N, 13.71 3~ 2-Nitro-6-[2-(4-trifluoromethyl-benzylamino)-ethoxy]-phenylamine as an orange solid (86.7 %)) mp 64-66 °C.
Elemental analysis for C16H16F3N3~3:
Calc'd: C, 54.09; H, 4.54; N, 11.83 is 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 EI m/e 315 (M') 2o Elemental analysis for C17H21N303 0.25 H20:
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 3o solution of hydrazine hydrate (0.6 mL) in ethanol (6.0 mL). The mixture was heated to 55-60 °C and stirred at that temperature for 16 hr. 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 diluted with ethyl acetate ( 100 mL). The organic Iayer was washed with water (2X, 100 mL) and brine ( 100 mL), dried over anhydrous magnesium sulfate, 3s 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.

This general procedure utilizing 2-[2-(4-methyl-benzylamino)-ethoxy]-6-nitro phenylamine (~, 2-nitro-6-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy}-phenylamine (3c), 2-{2-[(naphthalen-1-ylmethyl)-amino]-ethoxy}-6-nitro-phenylamine (3d), 2-[2-(3,4 dihydro- 1H-isoquinolin-2-yl)-ethoxy]-6-nitro-phenylamine (~, and 2-(3-benzylamino s propoxy)-6-nitro-phenylamine (3f) afforded:
4b 3-[2-(4-Methyl-benzylamino)-ethoxy]-benzene-1,2-- diamine as a off white solid (79.4 %), mp 77-79 °C; MS EI mle 271 (M').
to Elemental analysis for C16H21N30:
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 amber-is colored oil (70.0 %); MS EI mle 263 (M').
4d 3-(2-[(Naphthalen-1-ylmethyl)-amino]-ethoxy}-benzene-1,2-diamine quarterhydrateas a black oil (82.0 %); MS EI mle 307 (M').
2o Elemental analysis for C19H21N30 ~ 0.25 H20:
Calc'd: 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}-benzene-1,2-diamine as a solid 2s (95 %), mp 7b-77 °C. This material was characterized as the dihydrochloride 0.4 H20 salt MS EI mle 283 (M+) Elemental analysis for C 17H21 N30 ~ 2 HCI ~ 0.4 H20:
Calc'd: C, 56.17; H, 6.60; N, 11.56 3o Found: C, 56.15; H, 6.68; N, 11.25 4f 3-(3-Benzylamino-propoxy)-benzene-1,2-diamine as an amber-colored oil; MS
EI
mle 271 (M').
3s Elemental analysis for C16H21N30 ~ 0.3 H20:
Calc'd: C, 69.44; H, 7.87; N, 15.18 Found: C) 69.47; H, 7.82; N, 15.30 This general procedure utilizing 2-[2-(4-chloro-benzylamino)-ethoxy]-4-chloro-nitro-phenylamine (~h and Raney nickel in place of 10 % Pd/C afforded:
~ 3-[2-(4-chloro-benzylamino)-ethoxy]-4-chloro-benzene-1,2-diamine as a light-tan colored solid (75.0 %), mp 109-110 °C.
Elemental analysis for C15H17C12N30:
Calc'd: C, 55.23; H, 5.25; N, 12.88 to Found: C, 55.04; H, 5.09; N, 12,62 4h 3-[2-(4-Fluoro-benzylamino)-ethoxy]-benzene-1,2-diamine as a white solid (82.4 %), mp 70-71 °C.
i s Elemental analysis for C 1 SH 18FN30 0.1 H20:
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 2o 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 3-[2-(3-phenyl-propylamino)-ethoxy]-benzene-1,2-diamine as an oil (76.2 %); MS
(+)FAB m/e 286 (M+H+).
Intermediate Sa N-[2-(2-Amino-3-vitro-phenyoxy)-ethyl]-N-benzyl-2,2,2-trifluoro acetamide To a solution containing 2-(2-benzylamino-ethoxy)-6-vitro-phenylamine (3a, 0.50 3 s g, 1.74 mmol), triethylamine (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 mL) and extracted with methylene chloride. The 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 °C; MS EI mle 383 (M').
Elemental analysis for C17H1~,F3N304:
Calc'd: C, 53.27; H, 4.21; N, 10.96 Found: C, 53.09; H, 4.35; N, 10.93 i o This general procedure utilizing 2-(2-benzylamino-ethoxy)-4-chloro-6-nitro-phenylamine 3(~ afforded:
Sb N-[2-(2-Amino-5-chloro-3-nitro-phenoxy)-ethyl]-N-benzyl-2,"2-trifluoro-acetamide as a yellow solid (76.9 %), mp 106-I08 °C; MS (+)FAB mlc 418/420 (M+H)'.
is Elemental analysis for C17H15C1F3N304:
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-trifluoro-acetamide 2s To a mixture containing N-[2-(2-amino-3-nitro-phenyoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide 5a, 0.4 g) 1.04 mmol), 10% palladium on carbon (0.1 g) in ethanol (30 mL) was slowly added a solution of hydrazine hydrate (0.6 mL) in ethanol ( 10.0 mL).
The mixture was heated to 55-60 °C and stirred at that temperature for 1 hr. The mixture 3o was cooled to 25 °C, filtered and the catalyst was washed with ethanol. The filtrate was concentrated under vacuum and the residue was diluted with ethyl acetate (I00 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 mle 3s (M+H)'.

This general procedure utilizing N-[2-(2-amino-S-chloro-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide (Sb) 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 EI mle 387/389 (M+).
Elemental analysis for C17H117CIF3N302:
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-vitro-phenylamine A solution of 2-(2-chloro-ethoxy)-6-vitro-phenylamine (2a, 30.0 g, 0.14 mol), N-chlorosuccinamide 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 °C; MS EI mle 250/252/254 (M+).
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 ( l, 0.39g, 1.98mo1) and benzyl-amine (9 mL) was heated at 100-110° C for 3.5hr. The solvent was concentrated under vacuum (50-60°C/0.1 mmHg ( 13.3 Pa))) 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 (-rinrn f'~:~H
A1.~C;~rtl_~

AHP-9b 118 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 EI mle 267 (M+).
Elemental analysis for C 16H 17N30 ~ 2HCl ~ O.SH20:
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-1 H-benzoimidazol-4-yloxy)-ethyl]-amine A solution of 3-(2-benzylamino-ethoxy)-benzene-1,2-diamine (4a, 0.35 g, 1.36 mmol) and acetic acid ( 10 mL) was refluxed for 14 hr. The solvent was concentrated under vacuum (SO - 60° C / 0.1 mm Hg ( 13.3 Pa)) and the residue was dissolved in ethyl acetate (50 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 1N hydrogen chloride to give the title compound (0.33 g, 90.0 %) as a white solid, mp >250° C; MS EI mle 281 (M+).
Elemental analysis for C 17H 19N30 ~ 2HCl:
Calc'd: C, 57.63; H, 5.97; N, 11.61 Found: C, 57.23; H, 5.89; N, 12.86 APAEfVDED '~;~Ei 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-2,2,2-trifluoro-acetamide (6a, 1.0 g, 2.83 mmol) and trifluoroacetic acid ( 10-rrlL.) 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-1 H-benzoimidazol-4-yloxy)-ethyl]-acetamide as a tan-colored solid foam; MS EI mle 431 (M+).
A mixture of N-benzyl-2,2,2-trifluoro-N-[2-(trifluoromethyl-1 H-benzoimidazol-yloxy)-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-(2-tril7uoromethyl-1 H-benzoimidazol-4-yloxy)-ethyl]-amine ~ 0.25 ethyl acetate as a white solid, mp 130-131 °C; MS EI mle 335 (M+).
Elemental analysis for C 17H 16F3N30 ~ 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-1H-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 1 N hydrogen chloride to give the title compound (0.35 g, 79.1 %) as a white solid, mp 194-195 °C; MS EI mle 335 (M+).
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 ~iA!F'v~ rr' ~-~ ~-n ~

Example 4 (4-Methyl-benzyl)-[2-(2-trifluoromethyl-1H-benzoimidazol-4-yloxy) ethyl]-amine io The general procedures used in example 2 utilizing 3-[2-(4-methyl-benzylamino)-ethoxy)-benzene-1,2-diamine (~ and trifluoroacetic acid afforded:
(4-Methyl-benzyl)-[2-(2-trifluoromethyl-1 H-benzoimidazol-4-yloxy)-ethyl]-amine 0.25 ethyl acetate as a white solid (60.5 %), mp 154-158 °C; MS EI mle 349 (M+).
Elemental analysis for C 1 gH 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 is (4-Methyl-benzyl)-[2-(2-trifluoromethyl-1H-benzoimidazol-4-yloxy)-ethyl]-amine dihydrochloride as a white solid (90.1 %), mp 230-233 °C; MS EI
mle 349 (M').
Elemental analysis for CI gH18F3N30 ~ 2HC1:
Calc'd: C, 51.20; H, 4.77; N, 9.95 2o Found: C, 50.92; H, 4.69; N) 9.89 Example 5 25 [2-(2-Benzyl-1H-benzoimidazol-4-yloxy)-ethyl]- (4-methyl-benzyl)-amine The general procedures used in example 2 utilizing 3-[2-(4-methyl-benzylamino)-ethoxy]-benzene-1,2-diamine (,4~b and phenylacetic acid afforded:
30 [2-(2-Benzyl-1H-benzoimidazol-4-yloxy)-ethyl)-(4-methyl-benzyl)-amine dihydrochloride as a white solid (65.8 %), mp >250 °C; MS EI mle 371 (M+).
Elemental analysis for C24H25N3~ ~ 2HC1:
Calc'd: C, 64.86; H, 6.12; N, 9.46 3s Found: C, 64.43; H, 6.15; N, 9.31 Example 6 s (4-Methyl-benzyl)-{2-[2-(1,1,2,2,2-pentafluoro-ethyl}-1H-benzoimidazol 4-yloxy]-ethyl}-amine The general procedures used in example 2 utilizing 3-[2-(4-methyl-benzylamino)-ethoxy]-benzene-1,2-diamine (~ and pentafluoropropionic acid afforded:
(4-Methyl-benzyl)- { 2-[2-( 1,1,2,2,2-pentafluoro-ethyl)-1 H-benzoimidazol-4-i o yloxy]-ethyl }-amine 1.25 hydrate as a white solid (75.3 %) mp 85-90 °C decomposed;
MS EI mle 399 (M').
Elemental analysis for C19H18FSN30 ~ 1.25 H20:
Calc'd: C, 54.09; H, 4.90; N, 9.96 is Found: C, 53.83; H, 4.65; N, 9.76 (4-Methyl-benzyl)-{ 2-[2-(1,1,2,2,2-pentafluoro-ethyl)-1 H-benzoimidazol-4-yloxy]-ethyl }-amine hydrochloride as a white solid (79.7 %) mp 180 °C
decomposed; MS
EI mle 399 (M').
Elemental analysis for C19H18FSN30 ~ HC1:
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-benzoimidazol-4-yloxy) ethyl]-amine The general procedures used in example 2 utilizing 3-{ 2-[(thiophen-2-ylmethyl)-amino]-ethoxy } -benzene-1,2-diamine ~) and trifluoroacetic acid afforded:
Thiophen- 2-ylmethyl-[2-(2-trifluoromethyl-1H-benzoimidazol-4-yloxy)-ethyl]-3 s amine 1.6 Hydrochloride as a tan solid (58.3 % ), mp 184 °C; MS EI
ml a 341 (M+).
Elemental analysis for C18H18F3N30 ~ 1.6HC1:

WO 98/35945 YC'T/US98/OO613 -Calc'd: C, 44.98; H, 4.04; N, 10.38 Found: C, 44.99; H, 4.05; N, 10.33 s Example 8 Benzyl-[3-(2-trifluoromethyl-1H-benzoimidazol-4-yloxy)-propyl]-amine The general procedures used in example 2 utilizing 3-(3-benTylamino-propoxy)-lo benzene-1,2-diamine (4f) and trifluoroacetic acid afforded:
Benzyl-[3-(2-trifluoromethyl-1H-benzoimidazol-4-yloxy)-propyl]-amine hemi hydrate as a tan solid foam (57.6 %), mp 50-70 °C; MS EI mle 349 (h'(' ).
is Elemental analysis for C18HI8F3N30 ~ 0.5 H20:
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-1H-benzoimidazol-4-yloxy)-propyl ]-amine 2o Dihydrochloride as a white solid (98.0 %), mp 194-197 °C; MS EI m~e 349 (M+).
Elemental analysis for CIgHI8F3N30 ~ 2 HCI:
Calc'd: 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-pentaftuoro-ethyl)-1H-benzoimidazol-4-yloxy]-3o ethyl}-amine The general procedures used in example ~ utilizing N-[2-(1,2-diamino-benzene-3-yloxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide (6a) and pentafluoropropionic acid afforded:
3s Benzyl- ( 2-[2-( 1,1,2,2,2-pentafluoro-ethyl)- I H-benzoimidazol-4-yloxy]-ethyl } -amine as a white solid (59.8 %), mp 152-153 °C; MS EI mle 385 (M+).

Elemental analysis for C18H16FSN30:
Calc'd: C, 56.11; H, 4.19; N, 10.91 Found: C, 56.02; H, 4.10; N, 10.73 s Benzyl-{ 2-[2-(1,1,2,2,2-pentafluoro-ethyl)-1H-benzoimidazol-4-yloxy]-ethyl }-amine hydrochloride 0.75 hydrate as a white solid (69.4 %), mp 120-135 °C; MS (+)ESI
mle 386 (M+H+) Elemental analysis for C18H16FSN30 ~ HCl ~ 0.75 H20:
Calc'd: C, 49.67; H, 4.28; N, 9.65 Found: C, 49.88; H, 3.95; N, 9.66 is Example 10 Naphthalen-1-ylmethyl-[2-(2-trifluoromethyl-1H-benzoimidazol-4-yloxy]
ethyl]-amine The general procedures used in example 2 utilizing 3-{2-[(naphthalen-1-ylmethyl)-amino]-ethoxy}-benzene-1,2-diamine (4d) and trifluoroacetic acid afforded:
Naphthalen-1-ylmethyl-[2-(2-trifluoromethyl-1H-benzoimidazol-4-yloxy]-ethyl]-2s amine as a white solid (63.1 %), mp 130-133 °C; MS EI 385 mle (M+).
Elemental analysis for C21H18F3N30: .
Calc'd: C, 65.45; H, 4.71; N, 10.90 Found: C, 65.28; H, 4.43; N, 10.57 Naphthalen-1-ylmethyl- [2-(2-trifl uoromethyl-1 H-benzoimidazol-4-yloxy] -ethyl] -amine hydrochloride as a white solid (94.8 %)) mp 208-209 °C; MS El mle 385 (M+).
Elemental analysis for C18H18F3N30 ~ HCI:
3s Calc'd: C, 59.79; H, 4.54; N, 9.96 Found: C) 59.39; H, 4.45; N, 9.81 _...._.___~.-.. , Example 11 Thiophen-2-ylmethyl-[2-(1H-benzoimidazol-4-yloxy)-ethyl]-amine s The general procedures used in example 2 utilizing 3- { 2-[ (thiophen-2-ylmethyl)-amino]-ethoxy)-benzene-1,2-diamine (4c) and formic acid afforded:
Thiophen-2-ylmethyl-[2-( 1 H-benzoimidazol-4-yloxy)-ethyl]-amine quarter hydrate to as a viscous yellow oil (63.2 %); MS EI mle 273 (M~).
Elemental analysis for C14H15N3~S ~ 0.25 H20:
Calc'd: C, 60.52; H, 5.62; N) 15.12 Found: C, 60.85; H, 5.49; N, 15.39 is Thiophen-2-ylmethyl-[2-( 1 H-benzoimidazol-4-yloxy)-ethyl]-amine dihydrochloride hemihydrate as a white solid (69.2 %), mp 248-252 °C decomposed; MS El mle 273 (M+).
Elemental analysis for C 14H 15N3~S ~ 2.0 HCl ~ 0.5 H20:
2o 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)-1H
benzoimidazol-4-ytoxy)-ethyl}-amine The general procedures used in example 2 utilizing 3-[2-(4-methyl-benzylamino)-3o ethoxy]-benzene-1,2-diamine (~ and heptafluorobutyric acid afforded:
(4-Methyl-benzyl)- { 2-[2-(1,1,2,2,3,3,3-heptafluoro-propyl)-1H-benzoimidazol-yloxy]-ethyl }-amine as a white solid (63.7 %) mp 144-146 °C; MS EI mle 449 (M+).
Elemental analysis for C2pH18F7N30:
3s Calc'd: 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-propyl)-1H-benzoimidazol-yloxy]-ethyl}-amine 1.5 hydrochloride as a white solid (87.6 %) mp 198-199.5 °C; MS EI
mle 449 (M').
s Elemental analysis for C19H18F~N30 ~ 1.5 HCI:
Calc'd: C, 47.66; H, 3.90; N, 8.34 Found: C, 47.47; H, 3.76; N, 8.24 to Example 13 2-[2-(2-Trifluoromethyl-1H-benzoimidazol-4-yloxy-ethyl]-1,2,3,4 tetrahydro-isoquinoline 1 s The general procedures used in example 2 utilizing 3-[2-(3,4-dihydro-1 H
isoquinolin-2-yl)-ethoxy]-benzene-1,2-diamine (~ and trifouoroacetic acid afforded:
2-[2-(2-Trifluoromethyl-1 H-benzoimidazol-4-yloxy)-ethyl]-1,2,3,4-tetrahydro-isoquinoline quarter hydrate as a white solid (95.8 %) mp 168-171 °C;
MS EI mle 361 20 (M+).
Elemental analysis for C19H18F3N3~' x.25 H20:
Calc'd: C, 62.37; H, 5.10; N, 11.49 Found: C, 62.52; H, 4.85; N, 11.50 2-[2-(2-Trifluoromethyl-1H-benzoimidazol-4-yloxy)-ethyl]-1,2,3,4-tetrahydro-isoquinoline dihydrochloride as a white solid (94.3 %) mp 210-214 °C
decomposed; MS
EI mle 361 (M+).
3o Elemental analysis for C19H18F3N30 ~ 2 HCI:
Calc'd: C, 52.55; H, 4.64; N, 9.68 Found: C, 52.20; H, 4.81; N, 9.33 ..-~m.~.....w.~_....-...-.~,..... .~

Example 14 Benzyl-[2-(6-chloro-2-trifluoromethyl-1H-benzoimidazol-4-yloxy)-ethyl amine s The general procedures used in example ~, utilizing N-benzyl-N-[2-(2,3-diamino-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-acetamide (6bJ and trifluoroacetic acid afforded:
Benzyl-[2-(6-chloro-2-trifluoromethyl-1H-benzoimidazol-4-yloxy)-ethyl-amine as io a white solid (76.4 %), mp 171-172 °C; MS EI mle 369 (M+).
Elemental analysis for C17H15C1F3N30:
Calc'd: C, 55.22; H, 4.09; N) 11.36 Found: C, 55.05; H, 3.91; N, 11.13 ~s Benzyl-[2-(6-chloro-2-trifluoromethyl-1H-benzoimidazol-4-yloxy)-ethyl-amine as a white solid (73.4 %), mp 210-212 °C; MS EI mle 369 (M").
Elemental analysis for CI7H15C1F3N3(~ ~ HCI:
2o Calc'd: C) 50.26; H, 3.97; N, 10.34 Found: C, 50.29; H, 3.81; N, 10.32 Example 15 2s 4-Chlvro-benzyl-[2-(6-chloro-2-trifluoromethyl-1H-benzoimidazol-4-yloxy)-ethyl-amine The general procedures used in example 2 utilizing 3-[2-(4-chloro-benzylamino)-ethoxy]-4-chloro-benzene-I,2-diamine (~) and trifluoroacetic acid afforded:
4-Chloro-benzyl-[2-(6-chloro-2-trifl uoromethyl-1 H-benzoimidazol-4-yloxy)-ethyl-amine fumatate as a light-gray colored solid (79.6 %), np 191-193 °C;
MS EI mle 403/405/407 (M").
3s Elemental analysis for C17H14C13F3N30 ~ C~04:
Calc'd: 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-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:
to (4-Fluoro-benzyl)-2[2-(2-trifluoromethyl-1H-benzoimidazol-4-yloxy)-ethyl]-amine hydrochloride hemihydrate as a white solid {50.4 %), mp 225-227 °C; MS
EI mle 353(M+).
Elemental analysis for C17H15F4N30~1.0 HCl~0.5 H20:
1 s Calc'd: C, 51.20; H, 4.30; N, 10.54 Found: C, 51.06; H, 3.93; N, 10.35 Example 17 20 [2-(2-Trifluoromethyl-1H-benzoimidazol-4-yloxy)-ethyl]-(4-trifluoromethyl-benzyl)-amine The general procedures used in example 2 utilizing 3-[2-(4-trifluoromethyl-benzylamino)-ethoxy]-benzene-1,2-diamine (4i) and trifluoroacetic acid afforded:
[2-(2-Trifluoromethyl-1 H-benzoimidazol-4-yloxy)-ethyl]-(4-trifluoromethyl-benzyl)-amine hydrochloride as a white solid (80.5 %), mp 188-190 °C;
MS (+)FAB mle 404 (M+H+).
3 o Elemental analysis for C 1 gH 1 SF6N30~ 1.0 HCI:
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/OObl3 -Example 18 (3-Phenyl-propyl)-[2-(2-trifluoromethyI-1H-benzoimidazol-4-yloxy) ethyl J-amine s 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 °C; MS (+)FAB mle 364 (M+H+).
to Elemental analysis for C19H2pF3N3U 1.0 HC1:
Calc'd: C, 57.07; H, 5.29; N, 10.51 Found: C) 56.89; H, 5.15; N) 10.28 ~ s 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, 2o 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 2s 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 3H-quinpirole (Quip.) and various concentrations of test compound, filtered and washed and counted in a Betaplate scintillation counter.
3o 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 3H-spiroperidol (Spiper.) and various concentrations of test compound, filtered and washed and shaken with Hydrofluor 3s scintillation cocktail (National Diagnostics) and counted in a Packard 460 CD scintillation counter.

The results of the tests with compounds representative of this invention are given in the immediately following table.
Example IC50 (nM) ICSp (nM) Ratio No. D2 Quin. D2 Spiper 1 26.75 - -2 8.85 339 38.3 3 0.36 23.7 65.8 4 0. 7 4 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.I2 118.0 23.0 13 8.00 314.4 39.4 14 1.42 150.5 106 15) 7.77 395.0 50.8 16 0.74 49.0 66.2 17 1.16 87.0 75.0 18 0.56 - -s 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, ***e 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 is Garner 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 s 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 1 o 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.
is cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. 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 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.
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 so 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 3s psychosis and the size, age and response pattern of the patient.

Claims

CLAIMS:

(1) A compound of Formula I:
wherein:
R1 is hydrogen, 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, and C1-C6 alkoxy;
R2 is hydrogen or C1-C6 alkyl;
R3 is hydrogen, straight-chain or branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl, -(CH2)m Ar where Ar is phenyl, thienyl, furanyl, or pyridinyl, each optionally substituted by one to two substituents selected from halogen, C1-C6 alkoxy, trifluoromethyl and C1-C6 alkyl, and m is 1-3;
or NR2R3 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;
n is 1-5;
provided that when R1 is aminomethyl and Y is hydrogen, R2 and R3 are not both hydrogen;
or a pharmaceutically acceptable salt thereof.
(2) A compound according to claim 1 wherein R3 is benzyl, substituted benzyl, thienylmethyl, tetrahydroisoquinoline, furanylmethyl, phenylbutyl, or cyclohexylmethyl, and R1 is trifluoromethyl or pentafluoroethyl.
(3) A compound according to claim 1 which is [2-(1H-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-1H-benzoimidazol-
4-yloxy)-ethyl)-amine or a pharmaceutically acceptable salt thereof.
(5) A compound according to claim 1 which is benzyl-[2-(2-trifluoromethyl-1H-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-1H-benzoimidazol-4-yloxy)-ethyl)-amine or a pharmaceutically acceptable salt thereof.
(7) A compound according to claim 1 which is [2-(2-benzyl-1H-benzoimidazol-4-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-(1,1,2,2,2-pentafluoro-ethyl)-1H-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-trifluoromethyl-1H-benzoimidazol-4-yloxy)-ethyl]-amine or a pharmaceutically acceptable salt thereof.
(10) A compound according to claim 1 which is benzyl-[3-(2-trifluoromethyl-1H-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-ethyl)-1H-benzoimidazol-4-yloxy]-ethyl}-amine or a pharmaceutically acceptable salt thereof.
(12) A compound which is Naphthalen-1-ylmethyl-[2-(2-trifluoromethyl-1H-benzoimidazol-4-yloxy]-ethyl]-amine or a pharmaceutically acceptable salt thereof.
(13) A compound according to claim 1 which is thiophen-2-ylmethyl-[2-(1H-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)-1H-benzoimidazol-4-yloxy]-ethyl}-amine or a pharmaceutically acceptable salt thereof.
(15) A compound according to claim 1 which is 2-[2-(2-trifluoromethyl-1H-benzoimidazol-4-yloxy-ethyl]-1,2,3,4-tetrahydro-isoquinoline or a pharmaceutically acceptable salt thereof.
(16) A compound according to claim 1 which is benzyl-[2-(6-chloro-2-trifluoromethyl-1H-benzoimidazol-4-yloxy)-ethyl]-amine or a pharmaceutically acceptable salt thereof.
(17) A compound according to claim 1 which is 4-chloro-benzyl-[2-(6-chloro-2-trifluoromethyl-1H-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-1H-benzoimidazol-4-yloxy)-ethyl]-amine or a pharmaceutically acceptable salt thereof.
(19) A compound according to claim 1 which is [2-(2-trifluoromethyl-1H-benzoimidazol-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-1H-benzoimidazol-4-yloxy)-ethyl]-amine or a pharmaceutically acceptable salt thereof.
(21) A compound of Formula I:
wherein:
R1 is hydrogen, 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, vitro, hydroxy, and C1-C6 alkoxy;
R2 is hydrogen or C1-C6 alkyl;
R3 is hydrogen, straight-chain or branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl, -(CH2)m Ar where Ar is phenyl, thienyl, furanyl, or pyridinyl, each optionally substituted by one to two substituents selected from halogen, C1-C6 alkoxy, trifluoromethyl and C1-C6 alkyl and m is 1-3;
or NR2R3 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;
n is 1-5;
provided that when R1 is aminomethyl and Y is hydrogen, R2 and R3 are not both hydrogen;
or a pharmaceutically acceptable salt thereof, for use as a medicament.
(22) A compound according to claim 21 for use as a medicament in the treatment of diseases in a mammal which respond to treatment with dopamine D2 agonists.
(23) A compound according to claim 21 for use as a medicament in the treatment of schizophrenia.
(24) A compound according to claim 21 for use as a medicament in the treatment of Parkinson's disease.
(25) A compound according to claim 21 for use as a medicament in the treatment of Tourette's syndrome.
(26) A compound according to claim 21 for use as a medicament in the treatment of drug or alcohol addiction.

(27) 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, and C1-C6 alkoxy;
R2 is hydrogen or C1-C6 alkyl;
R3 is hydrogen, straight-chain or branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl, -(CH2)m Ar where Ar is phenyl, thienyl, furanyl, or pyridinyl, each optionally substituted by one to two substituents selected from halogen, C1-C6 alkoxy, trifluoromethyl and C1-C6 alkyl and m is 1-3;
or NR2R3 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;
n is 1-5;
or a pharmaceutically acceptable salt thereof.
(28) The method of treatment according to claim 27 wherein the disease treated is schizophrenia.
(29) The method of treatment according to claim 27 wherein the disease treated is Parkinson's disease.
(30) The method of treatment according to claim 27 wherein the disease treated is Tourette's syndrome.
(31) The method of treatment according to claim 27 wherein the disease treated is drug or alcohol addiction.
(32) A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the Formula wherein:
R1 is hydrogen, 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, and C1-C6 alkoxy;
R2 is hydrogen or C1-C6 alkyl;
R3 is hydrogen, straight-chain or branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl, -(CH2)m Ar where Ar is phenyl, thienyl, furanyl, or pyridinyl, each optionally substituted by one to two substituents selected from halogen, C1-C6 alkoxy, trifluoromethyl and C1-C6 alkyl and m is 1-3;
or NR2R3 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;
n is 1-5;
provided that when R1 is aminomethyl and Y is hydrogen, R2 and R3 are not both hydrogen;
or a pharmaceutically acceptable salt thereof.
(33) Use 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, and C1-C6 alkoxy;
R2 is hydrogen or C1-C6 alkyl;

R3 is hydrogen, straight-chain or branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl, -(CH2)m Ar where Ar is phenyl, thienyl, furanyl, or pyridinyl, each optionally substituted by one to two substituents selected from halogen, C1-C6 alkoxy, trifluoromethyl and C1-C6 alkyl and m is 1-3;
or NR2R3 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;
n is 1-5;
or a pharmaceutically acceptable salt thereof; in the manufacture of a medicament for the treatment of diseases in a mammal which respond to treatment with dopamine D2 agonists.