AU744443B2 - 4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-one derivatives, their preparation and their use as dopamine autoreceptor (D2) agonists - Google Patents

Description

4-AMINOALKOXY-1,3-DIHYDROBENZOIMIDAZOL-2-ONE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS DOPAMINE AUTORECEPTOR (D2)

AGONISTS

Field of Invention This invention relates to a series of 4-aminoalkoxy-1,3-dihydrobenzoimidazol- 2-ones having dopaminergic properties and thus have utility in treating Parkinson's disease, Tourette's syndrome, schizophrenia, and alcohol and drug addiction.

Background of the Invention The compounds of this invention are dopamine agonists having various degrees of intrinsic activity and are essentially free from extrapyramidal side effects.

Some of the compounds are selective autoreceptor agonists, and therefore partial agonists activate only autoreceptors versus postsynaptic D 2 dopamine receptors).

Efforts to induce antipsychotic activity with dopamine autoreceptor agonists have been successful (Dorsini et al., Adv. Biochem. Psychopharmacol., 16, 645-648, 1977; Tamminga et al., Science, 200, 567-568; and Tamminga et al., Psychiatry, 398-402, 1986).

Throughout the description and claims of this specification the word "comprise" 20 and variations of that word, such as "comprises" and "comprising", are not intended to exclude other additives or components or integers.

As selective autoreceptor agonists, the invention compounds 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 25 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 provides 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, as full agonists.

As such, they are useful in the treatment of diseases having abnormal concentrations RAZ, of dopamine could be used as dopamine surrogates such as schizophrenia,

L

1A Parkinson's disease and Tourette's syndrome. Such agents are partial agonists at the postsynaptic dopamine D 2 receptor and are thereby useful in the treatment of alcohol and drug addiction.

In the Belgian patent 850,166, Ciba-Geigy discloses compounds represented by the compound of the formula below which have both u and (-adrenergic properties and are useful as cardiovascular and antihypertensive agents.

go es e ooo*** oooo oooo o o oooo e *g* go oo 'C W:Nv*O D'G' NCOELTE 5957-3 1 HN 0Nl-t-lu NH OH 0 CGP-12177 Summary of the Invention Compounds of this invention are 4-aminoalkoxy- 1.3-dihydro-benzoimidazol-2s ones which are illustrated by Formula I below Y

R'

H I NR2 N H

N

to

I

S" wherein: R' is hydrogen or Ci-Cr, alkyl; R' is selected from hydrogen, straight-chain and branched Cr--Cjo alkyl, cyclohexylmethyl or -(Cl 2 )mAr where Ar is phenyl. naphthyl. thienyl, 15 furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from alkyl. halogen, alkoxide and Strifluoromethyl: or NR'R' is 1, 2, 3, 4-tetrahydroquinolin- 1-yl or 1, 2, 3, 4-tetrahydroisoquinolin- 2-yl; 20 mis n is 1 or 2;

R

3 is hydrogen or alkyl; Y is halogen, Ci-C 6 alkyl, CI-C 6 alkoxy and hydrogen and the pharmaceutically acceptable salts thereof.

Acid addition salts can be formed with an invention compound and a pharmaceutically acceptable acid including, but not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, acetate. fumarate. succinate.

citrate, maleate, lactate, and benzoate salts.

The compounds of this invention are dopamine autoreceptor agonists, that is. they serve to modulate the synthesis and release of the ncurotranmitter dopamine. They are thus -2- 9 useful for tamcnt of disorders of the dopanriincrgic system. such as schizophrcnia, Parkinson's disease and Touretc's syndrome. Such agents are partial agonists at the postsynaptic dopamine D 2 receptor and arc thcreby uscful in thc treatment of alcohol and drug addiction.

Detailed Description of the Invention The compounds of Formula I are generally prepared b) the overall sequence depicted in Schemes I -TV. Whcn one or both of R' and R' is hydrogen, it is desirable to protect the basic nitrogen with a suitable protecting group such as the trifluoroacccyl group to or t-butyloxycarbonyl group. Scheme I outlines a procedure to prepare an invention compound where R' is 11.

S

Scheme I n

R

2

NH

2 IrIfhi(1roacIcg N N 2 atiivdride o CF) I inL=I2 O CF 3

N,

O'"1n

&(NH

2

:NO

2 O CF 3

N

H

Il,NN[l2 10%7 Pd/lC Or Raney Nickel ethanol

O'(-TM

0

'R'

NH

2

T~~-NH

2 C111 T1It:l 1. K 2C0 3 MI-01 1/11 10 2. 1IicI

H

H

N

H

-3 WO 98/35946 PCT/US98/00623 Scheme II shows a synthetic route for invention compounds where R 3 is not H.

Scheme II OY CF3 n'-R trifluoroacetic

NH

2 anhydride N N0 2 0 <F 3 ,N R'

NHCOCF

3 bNO 2

R

3

X

DMSO

K

2 C0 3 0 ~<F 3

NR

3

COCF

3

K

2 C0 3

CNO

2 MeOlH20

H

NHR

3 N0 2 Boc 2 0 T

OC

NHR

3

H

2

NNH

2 N0 N 2 Pd/C 9OC 6

NHR

3

CDI

:NH

2 1. TFA 2. HC 9oc

N

H

Scheme III shows a synthetic route for invention compounds where neither of R' and R 2 is H.

4 rw;

I

WO 98/35946 PCT/US98/00623 Scheme III

NH

2

H

2

NNH

2

NO

2 10% Pd/C ethanol

NH

2

CDI

I

NH

2 HCI I H r^NM N =O HCI salt

H

Scheme IV shows the procedure used to prepare an intermediate where Y is Cl.

Scheme IV J^rNH 2 Cb:N02 2A

NCS

CH

3

CN

CNH

2 C 1- NO 2 The following specific examples illustrate the synthetic procedures for the preparation of intermediates and invention compounds and should not be construed as limiting the scope of this disclosure. Those skilled in the art of organic synthesis may be aware of still other routes to prepare invention compounds. Reactants and intermediates are either commercially available or can be prepared according to standard literature procedures.

Zk4rv WO 98/35946 PCT/US98/00623 Intermediate la 2-(2-Chloro-ethoxy)-6-nitro-phenylamine Method 1.

To a solution of 2-amino-3-nitrophenol (5.0 g, 32.4 mmol), triphenylphosphine (12.8 g, 48.7 mmol) and 2-chloroethanol (3.9 g, 48.7 mmol) in tetrahydrofuran (120 mL) at 0 50 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 18 hr. The solvent was removed under vacuum to give a dark brown oil. Purification by chromatography (1.3 kg silica gel, 30% hexane ethyl acetate) afforded 3.1 g of an orange solid, mp 71-73 MS (+)PBEI mle 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 Method 2.

A slurry containing 2-amino-3-nitrophenol (32.0 g, 0.208 mol), 1,2-dichloroethane (260.0 g, 2.65 mol), 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 (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 trituration of the residue with hexane afforded 37.8 g of product as an orange solid, mp 71-73 MS (+)PBEI m/e 216/218 Intermediate lb 2-(3-Bromo-propoxy)-6-nitro-phenylamine Following the procedure of method 2 above, and using 1,3-dibromopropane, the title compound was as a yellow solid, mp 88-89 MS El m/e 274/276 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 6 w WO 98/35946 PCT/US98/00623 Intermediate 2a 2-(2-Benzylamino-ethoxy)-6-nitro-phenylamine A mixture of 2-(2-chloro-ethoxy)-6-nitro-phenylamine (1a, 3.0 g, 13.8 mmol) and benzylamine (9.0 g, 84.0 mmol) was heated neat at 100-1100 C for 6 hr. The excess benzylamine was removed by distillation under vacuum (70-75 "C 0.1 mm) 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 me 287 Elemental analysis for C15H17N303: Calc'd: C, 62.71; H, 5.96; N, 14.62 Found: C, 62.64; H, 6.04; N, 14.23 'DMSO can be used as a solvent in this reaction Using this general procedure and utilizing 2-(2-chloro-ethoxy)-6-nitro-phenylamine or 2-(3-bromo-propoxy)-6-nitro-phenylamine or 4-chloro-2-(2-chloro- ethoxy)-6-nitrophenylamine and 4-methyl-benzylamine, 1 -naphthalene-methylamine, 4-tert-butylbenzylamine, thiophene-2-methyl-amine, 4-chloro-benzylamine, thiophene-3-methylamine, 1,2,3,4-tetrahydroisoquinoline or 3-phenyl-1-propylamine produced the following intermediates 2b-21, respectively: 2b 2-[2-(4-Methyl-benzylamino)-ethoxy]-6-nitro-phenylamine as a yellow solid (89 mp 55-57 El mle 301 Elemental analysis for C16H19N303: Calc'd: C, 62.71; H, 5.96; N, 14.62 Found: C, 62.64; H, 6.04; N, 14.23 2c 2-(3-Benzylamino-propoxy)-6-nitro-phenylamine as a viscous orange oil (85.5 MS El mle 301 Elemental analysis for C16H19N303: Calc'd: C, 63.77; H, 6.36; N, 13.94 7 r~ WO 98/35946 WO 9835946PCTIUS98/00623 Found: C, 63.66; H, 6.28; N, 13.89 2d 2 2 [(Napht halen- 1-yl met hyl)- amino]l-ethoxy} -6-nitro- phenylamine as a yellow solid (76.3 mp 66-67 MS El mle 337 Elemental analysis for Cl9Hl9N3O3' Calc'd: C, 67.64; H, 5.68; N, 12.45 Found: C, 67.20; H, 5.66; N, 12.26 2e 2-[2-(4-tert-Butylbenzylamino)-ethoxy]-6-nitro-phenylamine as an orange viscous oil (83.3 MS El mle 343 Elemental analysis for C19H125N303 -0.25 Calc'd: C, 65.59; H, 7.39; N, 12.07 Found: C, 65.89; H, 7.20; N, 11.94 2f 2 -Nitro-6-{2-[(thiophen-2-ylmcthyl)-amino].ethoxyl-phenylamine as a red semi -solid material (8 8.5 MS Elmr/e 389 Elemental analysis for C13H115N303S: Calc'd: C, 53.23; H, 5.15; N, 14.32 Found: C, 52.86; H, 4.93; N, 14.15 2g 2-[2-(4-Chloro-benzylamino)-ethoxy]-6-nitro-phenylamine as an orange solid (87.8 mp 61-62 MS El ml e 322/324 Elemental analysis for C1I5H1I6N303 0.25 Calc'd: C, 55.22; H, 5.10; N, 12.88 Found: C, 55.27; H, 4.96; N, 12.88 2h 2 2 -Benzylamino-ethoxy)-4-chloro-6-nitro-phenylamine as a orangebrown colored solid (54.0 mp 87-88 MS El mWe 32 1/323 Elemental analysis for C1 5H 1 6CIN303: Calc'd: C, 55.99; H, 5.01; N, 13.06 Found: C, 55.85; H, 4.90; N, 13.13 8 V C' 'd, WO 98/35946 PCT/US98/00623 i 4-Chloro-2-nitro-6-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy}phenylamine as a yellow solid (44.0 mp 74-75 MS El me 327/329 Elemental analysis for C13H14C1N302S: Calc'd: C, 47.67; H, 4.33; N, 12.75 Found: C, 47.54; H, 4.11; N, 13.06 S 4-Chloro-2-nitro-6-{2-[(thiophen-3-ylmethyl)-amino]-ethoxy}phenylamine as a yellow solid (33.3 mp 77-78 MS El mle 327/329 Elemental analysis for C 3H14CIN302S: Calc'd: C, 47.67; H, 4.33; N, 12.75 Found: C, 47.54; H, 4.18; N, 12.80 2k 2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethoxy]-6-nitro-phenylamine as a yellow solid (87.1 mp 95-97 MS El mle 313 Elemental analysis for C17H19N302: Calc'd: C, 65.16; H, 6.11; N, 13.41 Found: C, 64.87; H, 6.11; N, 13.40 21 2-Nitro-6--[2-(-phenyl-propylamino)-ethoxy]-phenylamine as a viscous orange oil MS El mle 315 Elemental analysis for C 17 F1 2 1

,N

3 0 3 *0.25 H 2 0: Calc'd: C, 63.83; H, 6.77; N, 13.14 Found: C, 63.90; H, 6.56; N, 13.07 Intermediate 3a N- [2-(2-Amino-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide To a solution of 2-(2-benzylamino-ethoxy)-6-nitro-phenylamine 0.5 g, 1.74 mmol) and triethylamine (0.32 mL, 3.48 mmol) in anhydrous methylene chloride (10 mL) at 230 C was added trifluoroacetic anhydride (0.32 mL, 2.26 mmol). After 2 hr the reaction was diluted with ether and washed with saturated sodium bicarbonate (3 x 80 mL) and the 9 P

I

WO 98/35946 PCT/US98/00623 organic layer dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave 0.55 g of yellow solid, mp 134-135 IC; 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.

Following this general procedure and using 2 4 -methyl-benzylamino)-ethoxy]- 6-nitro-phenylamine, 2-(3-benzylamino-propoxy)-6-nitro-phenylamine, 2- [(naphthalen- 1 -ylmethyl)-amino]-ethoxy I -6-nitro-phenylamine, 2-[ 2 -(4-tert-butylbenzylamino)-ethoxy]- 6-nitro-phenyl-amine, 2-nitro-6-(2- [(thiophen-2-ylmethyl)-amino]-ethoxy )-phenylamine, 2-[2-(4-chloro-benzylamino)-ethoxy]-6-nitro-phenylanine, 2-(2-benzylamino-ethoxy)-4chloro-6-nitro-phenylamine, 4-chloro-2-nitro-6 (2-l (thiophen-2-ylmethyl )-amino] ethoxy) -phenylamine, 4-chloro-2-nitro-6- (2-f(thiophen-3-ylmethyl)-aminoj-ethoxy) phenylamine and 2-nitro-6-2-(3-phenyl-propylamino)-ethoxy]-phenylamine gave respectively: 3b N-[2-(2-Amilo-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-(4-methyI.

benzyl) acetamide as a yellow solid (79 mp 172-173 MS El We/ 397 Elemental analysis for Ci 81H1 8F3N304: Calc'd: C, 54.41; H, 4.57; N, 10.58 Found: C, 54.34; H, 4.33; N, 10.53 3c N-[3-(2-Amino-3-nitro-phenoxy)-propyll-N-benzyl-2,2,2-trifluoro.

acetamide as a yellow solid (67.8 mp 92-93 MS El mle 397 Elemental analysis for C18H18F3N304: Calc'd: C, 54.41; H, 4.57; N, 10.58 Found: C, 54.30; H, 4.50; N, 10.50 3d N-[2-(2-Amino-3-nitro-phenoxy)-ethyll-2,2,2-trifluoro-Nnaphthalen-1-ylmethyl-acetamide as a yellow-orange colored solid (75.3 mp 133-135 MS EIme 433 Elemental analysis for C21Hi8F3N304: Calc'd: C, 58.20; H, 4.19; N, 9.70 1 WO 98/35946 PCITUS98/00623 Found: C, 58.28; H, 4.07; N, 9.48 3e N-[ 2 -(2-Amino-3-nitro-phenoxy)-ethyl]-N-(4-tert-butyl- benzyl)- 2,2,2-trifuoro-acetamide as a yellow solid (82.0 mp 80-82 MS El mle 439 Elemental analysis for C21H24F3N304: Calc'd: C, 57.40; H, 5.51; N, 9.56 Found: C, 57.09; H, 5.31; N, 9.40 io 3f N-[ 2 -(2-Amino-3-nitro-phenoxy)-ethyi]-2,2,2-trifluoro N-thiophen.

2-ylmethyl-acetamide as a yellow solid (77.4 mp 143-144 MS El mle 389 Elemental analysis for ClSHl4F3N304S: Calc'd: C, 46.27; H, 3.62; N, 10.79 Found: C, 46.19; H, 3.39; N, 10.64 3g N-[2-(2-Amino3-nitro-phenoxy)-ethyl].N(4chloro-benzyl)2,2,2trifuoro-acetamide as a yellow solid (84.0 mp 138-139 MS (+)FAB mie 418/420 Elemental analysis for C17H5ClF3N3O4: Calc'd: C, 48.88; H, 3.62; N, 10.06 Found: C, 48.66; H, 3.47; N, 9.82 3h N-[2-(2-Amino-5-chloro-3-nitro-phenoxy)-ethyl] -N -benzyl2,2,2 trifluoro-acetamide as a yellow solid (67.9. mp 106-108 MS (+)FAB me 418/420 Elemental analysis for C17H1SClF3N3O4: Calc'd: C, 48.88; H, 3.62; N, 10.06 Found: C, 48.96; H, 3.50; N, 10.03 3i N-[ 2 -(2-Amino-5-chloro-3-nitro-phenoxy)-ethyl]..2,2,2trifluoro-Nthiophen-2-ylmethyl-acetamide as a yellow solid (59.6 mp 97-98 MS El me 423/425 11 i~ii Elemental analysis for C, 5 1 i 13 C1FIN.10%S: Calc'd: C, 42.51:.1l. 3.09; N. 9.92 Found: C, 42.37-. H. 2.97;. N, 9.84 2ij

N.I

2 2 A nino ch o-ro-pnir thiophefl3-yImethyl-acetamide as a yellow solid (80.0 149-150 NIS l rn/c 423/425 Elemental analysis for CIS5"l 3 CFN--;O4S: Calc'd: C. 42.51. 11. 3.09: N, 9.92 Found: C, 42.02: 11. 2.95; N. 9.79 propy1)-acetamide as a yellow solid mnp, 8-S2 NIS El I~ I 1 Elemental analysis for C 1 9 1 kjj 3 V ~Calc'd: C. 55.47: 11. 4.90:. N, 10.21 Found: C. 55.57-. 4.66: 10.23 20 itrmei-l' 4 N~BelZV~~.2~2~d~minohe To a mixture of 2 4(2.ano3 itropheno\\ i-elhyl I -N eflz\ -I.2rifluoroacctainide (Ld. 2.4 g, 6.26 miniol) and 10 rC palladiu n 01r1 o C17-)I(0.40 lin ethanol (0 nL) at 50-55CC was added a solution of hvdralifc hydrate (2.0 g, in ethanol '25 illi. Thec reaction was allow,\ed to stir for 18 hr at '13'C. then thec caullyst filtered through solka. tl~v ::and the solvent removed tinder vacuufli to .afford 1.96 (88.9 of an amber-coloretI oil.

*Crystallization from ethyl acetate hexane gave a white solid. nip I I S 119

MS

30 rn/c 354 (MI+Il').

Elemental analysis for C 17111, 8 11N 302: Calced: C, 56.58. HI. 4.72: N. 12.3S Found: C. 57.49:. 1 L 5. 10; N. 11.86 Following the above procedure and utilizing N-I 2 -(2-aflino 3- nitro- phenoxv .ethl %1 2.2.2' trfur---mty-ezl acetamide. ,2ail3i~~eo~tpoy1 ~V~4vZ.~fre V %y- 4 -AC~V~r'w>5 ~.VVOrtW.t7.V~ WO 98/35946 WO 9835946PCTIUS98/00623 benzyl-2,2,2-trifluoro-acet~mide, N-[2-(2-amino-3-nitro-phenoxy)-ethyl] -2,2,2-trifluoro- N-naphthalen- 1-ylmethyl-acetamide, N- [2-(2-aniino-3-nitro-phenoxy)-ethyl]-N-(4-tertbutyl-benzyl)-2,2,2-trifluoro-acetamide, N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-2,2,2trifluoro-N-thiophen-2-ylmethyl-acetamide, N- (2-amino-3-nitro-phenoxy)-ethyl] chloro-benzyl)-2,2,2-trifluoro-acetamide, N-[2-(2-amino-5-chloro-3-nitro-phenoxy)ethyl] -N-benzyl-2,2,2- trifluoro-acetamide, N-[2-(2-amino-5-chloro-3-nitro-phenoxy)ethyl] -2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamiide, and N-[2-(2-amnino-5-chloro-3nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide afforded respectively: 4b N- [2 iamin o- phenoxy)- ethyl] -2,2,2-trifIl uoro-N -meth ylIbenzyl)-acetamide as a white solid (85.0 mp 94-96 MIS El mWe 367 Elemental analysis for C1I8H20F3N302: CaIc'd: C, 58.85; H, 5.49; N, 11.44 Found: C, 58.91; H, 5.32; N, 11.45 4c N-Benzyl.N-[3-(2,3-diamino-phenoxy)-propyll-2,2,2-trifluoroacetamide as a white solid (86.5 mp 56-58 MIS El mWe 367 Elemental analysis for C18H20F3N302: Calc'd: C, 58.85; H, 5.49; N, 11.44 Found: C, 59.00; H, 5.42; N, 11.48 4d N-[2-(2,3-Diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-naphthalen-1ylmethyl-acetamide as a viscous yellow oil (63.0 S (+)FAB mWe 404 Elemental analysis for C21H20F3N302: Calc'd: C, 62.53; H, 5.00; N, 10.42 Found: C, 62.45; H, 4.98; N, 10.20 4e N-(4-tert-Butyl-benzyl)-N-[2-(2,3-dianiino-phenoxy)-ethyl]-2,2,2trifluoro-acetamide as a viscous brown oil (72.7 MIS El Wle 409 4f N- [2-(2,3-Diamino- phenoxy) -ethyl] -2,2,2-trifluoro-N-thi op hen-2ylmethyl-acetamide as a white solid (41.0 mp 72-74 MIS (+)FAB mle 404 13 ~C .WO 98t35946 WO 9835946PCT/US98/00623 Elemental analysis for C15HI6F3N302S: Calc'd: C, 50.13; H, 4.49; N, 11.69 Found: C, 50.09; H, 4.38; N, 11.59 4g N-(4-Chloro bnyI--2 -23diamiophenoxy).ethy1.2,2,2.

tritluoro-acetamide as a brown oil (80.9 MS EL Wle 387/389 Elemental analysis for C 17HI17C1F3N302: Calc'd: C, 52.65; H, 4.42; N, 10.84 Found: C, 52.47; H, 4.51; N, 10.60 4h N-BenzyI-N-[2-(2,3-diamino-5-ch loro-phenoxy)-eths.ltI2,2,2trifluoro-acetamide as a viscous brown oil (76.2 MS El rn/c 387/389 Elemental analysis for Ci 7H 17C1F3N302: Calc'd: C, 52.65; H, 4.42; N, 10.84 Found: C, 52.47; H, 4.39; N, 10.90 4i N- [2 -(2,3-Diami no-5 -ch oro-phenoxy) -ethyl]2,2,2t ri f Iuoro-N thiophen-2-ylmethyl-acetamide as a viscous brown oil (71.4 MS El rn/c 393/395 Elemental analysis for Cl 5H15C1F3N302S: Calc'd: C, 45.75; H, 3.84; N, 10.67 Found: C, 45.58; H, 3.93; N, 10.64 4j N- Diamino-5-ch loro-phenoxy) -ethyl 2,2,2trifl uoro-Nthiophen-3-ylmethyl-acetamide as a viscous brown oil (75.0 MS El We/ 393/395 Elemental analysis for C1ISH1I5C1F3N3O02S: Calc'd: C, 45.75; H, 3.84; N, 10.67l Found: C, 45.39; H, 3.84; N, 10.56 Intermediate 14 ~t If' 'V WO 98t35946 WO 9835946PCTIUS98/00623 N-B enzyl-2,2,2-trifluoro-N- (2-oxo-2,3- di hydro- 1l- benzoimi dazol-4yloxy)-ethyl] -acetainide A mixture of N-benzyl-N-[2- (2,3-diamino-phenoxy)-ethyl] -2,2,2-trifluoroacetamide (0.28 g, 0.804 mmnol) and dilmnidazole carbonyl (0.326 g, 2.0 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at 230 C for 2 hr. The reaction was poured into water and extracted with ethyl acetate (2 x 150 miL). The organic layer dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum.

Purification by chromatography (60 g silica gel, ethyl acetate hexane :2 M NH3 in methanol (15 :5 afforded 0.29 g of a colorless oil. Crystallization from hexane gave a white solid, mp 121-123 MS El mWe 379 Elemental analysis for C I 8H I 6F3N303: Calc'd: C, 56.99; H, 4.25; N, 11.08 Found: C, 5 7.09; H, 4.07; N, 11. Utilizing N-[2-(2,3-diamino-phenoxy)-ethylI-2,2,2-trifluoro-N-(4-methyl-benzyl)acetamide, N-benzyl-N- [3-(2,3-diamino-phenoxy)-propyl]-2,2,2-trifluoro-acetamide,

N-

[2-(2,3-diamino-phenoxy)-ethyl] -2,2,2-trifluoro-N-naphthalen-1I-ylmethyl-acetamide,

N-

(4-tert-butyl-benzyl-N- [2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-acetamide, N- 2- (2,3-diamino-phenoxy)-ethyl] -2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide, N- (4chloro-benzyl)-N-[2-(2,3-diamiino-phenoxy)-ethyl] -2,2,2-trifluoro-acetamide, N-benzyl- N-[2-(2,3-diamino-5-chloro-phenoxy)-ethyl]- 2,2,2-trifluoro-acetamide, N- (2,3diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2 -ylmethyl-acetamide and N-[2-(2,3-diamino-5-chloro-phenoxy)-ethyl] -2,2,2-trifluoro-N-thiophen-3-ylmethylacetamide in the above general procedure afforded respectively: 2,2,2-T rifluoro-N -met hy- ben zy) (2-oxo-2,3 -d ihyd ro- 1H bcnzoimidazol-4-yloxy)-ethyl]-acetamide 0.1 ethyl acetate as a white solid (96.6 mp 194-196 MIS (+i)FAB mWe 394 Elemental analysis for C1I9H1I8F3N303 0. 1 C4H802 Calc'd: C, 57.94; H, 4.7 1; N, 10.45 Found: C, 57.90, H, 4.60, N, 10.19 WO 98/35946 PCTIUS98/00623 N-Benzyl-2,2,2-trifluoro.N-[3-(2-oxo-2,3-dihydroIH benzoimidazol-4-yloxy)-propyll-acetamide as a white solid (86.0 mp 114-116 MS (+)FAB mle 394 Elemental analysis for C19H1 8F3N303 Calc'd: C, 58.01; H, 4.61; N, 10.68 Found: C, 57.67; H, 4.37; N, 10.49 2,2,2-Trifluoro-N-naphthalen--ylmethyl-N-[2-(2-oxo-2,3-dihydro 0 1 H-benzoimidazol-4-yloxy)-ethyll-acetamide as a white solid (90.0 mp 88-90 MS El mle 429 Elemental analysis for C22H 1 8F3N303 Calc'd: C, 61.54; H, 4.23; N, 9.79 Found: C, 61.34; H, 4.25; N, 9.52 N-(4-tert-ButyI-benzyI)-2,2,2-trifluoro-N-[2-(2-oxo-2,3-dihydro- 1H-benzoimidazol.4-yloxy)-ethyl]-acetamide as a white solid (84.9 mp 184- 185 MS El mle 435 Elemental analysis for C22H24F3N303 Calc'd: C, 60.68; H, 5.55; N, 9.65 Found: C, 60.59; H, 5.55; N, 9.66 Sf 2,2,2-Trifluoro-N-[2-(2-oxo-2,3-dihydro.1H-benzoimidazol-4 yloxy)-ethyll-N-thiophen-2-ylmcthyl-acetamide as a white solid (73.3 mp 49-50 MS El mle 385 N-(4-Chloro-benzyl)-2,2,2-trifluoro-N- [2-(2-oxo-2,3.dihydro- lH.

benzoimidazoI-4-yIoxy)-ethyl]acetamide as a white solid (56.7 mp 190-192 MS (+)FAB mle 414/416 Elemental analysis for Cl 8H15CF3N303 Calc'd: C, 52.25; H, 3.65; N, 10.16 Found: C, 52.28; H, 3.55; N, 10.20 16 7 WO 98/35946 WO 985946PCT/US98/00623 N-BenzyI-N- (6-chloro-2-oxo-2,3- di hydro- H- benzoi midazol -4.

yloxy)-ethyl]-2,2,2-trifluoro-acetamide as a white solid (60.0 mp 171-173 *C; MIS (+)APCI Wle 414.2/416.2 Elemental analysis for C I8H 15CIF3N3O3 Calc'd: C, 52.25; H, 3.65; N, 10.16 Found: C, 52.10; H, 3.56; N, 9.96 Li N-[ 2 -(6-Chloro-2-oxo-2,3-dihydro-1H..benzoimidazol.4-yloxy)ethyl]- 2 ,2,2-trifnuoro-N-thiophen-2-ylmcthyl-acetainide as a white solid (70.1 %,mp 153-154 MS El Wle 419/421 Elemental analysis for Cl 6H1I3C1F3N303S: Calc'd: C, 45.78; H, 3.12; N, 10.0 1 Found: C, 45.85; H, 3.02; N, 9.73 N-[2-(-hlr--oxo-2,3.dihydro- I 11-benzoimidazol-4-yloxy)ethyl]- 2 2 2 tri flu oro-N-t hi ophen -3-y imet hyl -acetamid e as a white solid (77.8 mp 152-153 MS El mWe 419/421 Elemental analysis for C16H13C1F3N303S: Calc'd: C, 45.78; H, 3.12; N, 10.01 Found: C, 45.86; H, 2.93; N, 9.76 Intermediate 6 2 2 2 ,2-Trifluoroacetamidyl)-3-nitro-phenoxy).ethylI -N-benzyl- 2,2,2- tri flu oro- a cetarniide To a suspension of N- 2 amino- 3-nitro-phenoxy)-ethyl] N-benzylp2,2,2.

trifl uoro-acetamide (4.95 g, 12.9 mimol) in anhydrous methylene chloride (50 mL-) at room temperature was added trifluoroacetic anhydride (3.18 g, 15.1 mmol). After 15 min the reaction was diluted with ether and washed with saturated sodium bicarbonate (3x 80 mL) and the organic layer dried over anhydrous magnesium sulfate. Upon filtration and evaporation of the solvent gave 5.84 g of yellowish white solid, mp 114-115 *C; MS FAB Wle 480 17 WO 98/35946 PC/UJS98/00623 Elemental analysis for ClqH1SF6N3OS Calc'd: C, 47.6 1; H, 3.15; N, 8.77 Found: C, 47.35; H, 2.94; N, 8.69 Intermediate 7

N-[

2 -(l-Metby-2-{2,2,2-Trifluoroacetami dy} -3nitro.phenoxy).ethy]..N benzyl-2,2,2-trifluoro-acetamnide A suspension of potassium carbonate (1.44g, 10.4 mmol), trifluoroacetamnidyl) 3 -n itro-phenoxy) -ethyllI-N-be nzyl-2,2,2- tri fl uoro-acetamide (1.0 g, 2.09 mmol) and methyl iodide (2.96 g, 20.9 mmol, previously filtered through basic alumina) in anhydrous dimethylsulfoxide (I11 mL) was allowed to stir at room temperature for 24 h. The reaction mixture was poured into methylene chloride (200 miL) and extracted with water (2x 80 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to afford a yellow thick oil. Purification by chromatography (30% ethyl acetate-hexanes) afforded 960 mg (93.3 of a light yellow solid, mp 90-92.5 MS mie El 493 Elemental analysis for C20H 17F6N305 Calc'd: C, 48.70; H, 3.47; N, 8.57 Found: C, 48.50; H, 3.27; N, 8.39 Intermediate 8 N-Benzyi-2-(2-methylamino-3-nitro-p henoxy)-ethylaminc A suspension of potassium carbonate (2.52 g, 18.2 mmol) and N-[2-l-methyl-(2- (2,2,2-trifluoroacetamidyl I 3 -nitro-phenoxy)-ethylJ-N-benzyl-2,2,2.trifluoro-acetarnjde (900 mg, 1.82 mmol) in methanol-water (50 mL:3 mL) was heated to reflux for 2 h then the solvent was evaporated and the residue dissolved in methylene chloride (100 mL) and extracted with water (80 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum. The residue was further purified 18 I-m J I by passing through a short pad of silica to afford 505 ing (92.1 of N-bcnzyl-2- (methylamino-3-nitro-phenoxy)ethylamine as a red oil; MS FAB mnle/c 302 (M+11l).

Intermediate 9 N-Benzyl-[2-(2-methylamino-3fnitro-phenoxy)-ethy-carl)amic acid tertbutyl ester A solution of N-bcnzyl-2-(2-mcthylamino- 3-nitro- phcnoxy)-etihylanminec 1o (480 mg. 1.59 mmol) and di-tert-butyl dicarbonate (348 nimg 1.59 mmol) in anhydrous tetrahydrofuran (6 mL) was allowed to stir for 3 hr. The reaction mixture was poured into methylene chloride (80 mL) and washed with water (50 The organic layer dried over anhydrous magnesium sulfate. filtered, and the solvent evaporated to afford 593 mg (93 1) of an orange solid, mp 91-93 C; MS mc El 401 Elemental analysis for C211127N305 Calc'd: C. 62.83; 11, 6.78: N. 10.47 Found: C. 62.78: H1. 6.53: N, 10.51 Intermediate N-Benzyl-[2-(2-methylamino-3-amio-plenox ,.-ethyll-carbamic acid ter(b u t y l e s te r To a mixture of N-benzyl-12-(2-methylanilo-3-nitro-phenoxy)-etvyll-carbmic acid tert-butyl ester (520 mg, 1.30 mmol) and 10 palladium on carbon (120 mng) in ethanol (40 mL) at 50 OC was added a solution of hydrazine hydrate (1.3 g) in ethanol The reaction was allowed to stir for 3 hr then the catalyst filtered through celitee and 30 the solvent removed. Purification by chromatography (30 ethyl acetate-hexanc) affordedl 380 mg (78.9 of a clear oil: MS El nm/c 371 IR (film) 34(X). 3350. 1680 cm-1.

19 -I -r WO 98/35946 PCT/US98/00623 Intermediate 11 N-Benzyl-[2-(2-oxo- 1,3-dihydro-benzoimidazol-4-yloxy)-ethyl]-carbamic acid tert-butyl ester A mixture of N-benzyl-[2-(2-methylamino-3-amino-phenoxy)-ethyl]-carbamic acid tert-butyl ester (330 mg, 0.89 mmol) and diimidazole carbonyl (577 mg, 3.56 mmol) in anhydrous tetrahydrofuran (30 mL) was stirred a room temperature for 0.5 h and then heated to reflux for 3 h. The reaction was poured into water and extracted with ethyl acetate (2 x 150 mL). The organic layer dried over anhydrous magnesium sulfate, filtered, and the solvent removed. Purification by chromatography (50 ethyl acetate-hexane) afforded 268 mg (75.8 of a foam; MS FAB mle 398 IR (KBr) 3420, 3250, 1690 (bs) cm-1.

Intermediate 12 3-[2-(3,4-Dihydro-1H-isoquinolin-2-yli)-ethoxy]-benzcne-1,2-diamine The general procedure used in intermediate 4 using 2-[2-(3,4-dihydro-1Hisoquinolin-2-yl)-ethoxyl -6-nitro-phenylamine (2k) afforded 3-[2-(3,4-dihydro-1Hisoquinolin-2-yl)-ethoxy]-benzene- 1,2-diamine as a solid (95 mp 76-77 C. This material was characterized as the dihydrochloride 0.4 H20 salt; MS El mle 283 Elemental analysis for C17H21N30 2 HCI 0.4 Calc'd: C, 56.17; H, 6.60; N, 11.56 Found: C, 56.15; H, 6.68; N, 11.25 Intermediate 13 4-Chloro-2-(2-chloro-ethoxy)-6-nitro-phenylamine A solution of 2-(2-chloro-ethoxy)-6-nitro-phenylamine (la, 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 rnL), dried over r WO 98/35946 PCT/US98/00623 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 mle 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 4-(2-Benzylamino-ethoxy)-1,3-dihydro-benzoimidazol.2-one A suspension of potassium carbonate (1.15 g, 8.34 mmol) and N-benzyl-2,2,2trifluoro-N-[2-(2-oxo-1,3-dihydro- H-benzoimidazol-4-yloxy)-ethyl I-acetamide (0.38g, 1.00 mmol) in methanol-water (30 mL:2 mL) was heated to reflux for 2 hr then the solvent was evaporated and the residue dissolved in ethyl acetate (100 mL) and extracted with water (80 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give the title compound as a white solid, mp 132-135 0 C. Without further purification, this material was dissolved in ethyl acetatemethanol and treated with an excess amount of 1 N HCI in ether to afford 0.30g of the hydrochloride salt as a light tan-colored solid, mp 230-233 MS El m/e 283 Elemental analysis for C16H17N302-HC1 Calc'd: C, 60.09; H, 5.67; N, 13.14 Found: C, 59.84; H, 5.59; N, 12.92 Example 2 4-[2-(4-Methyl-benzylamino)-ethoxy]-1,3-dihydro-benzoimidazol-2-one Following the general procedure used in example 1 and utilizing 2,2,2-trifluoro-N- (4-methyl-benzyl)-N-[2-(2-oxo-2,3-dihydro- 1H-benzoimidazol-4-yloxy)-ethyl]-acetamide 0.1 ethyl acetate (5b) afforded the title compound as a white solid (64.5 mp 162-163 21 yf-^ f^ WO 98/35946 WO 9835946PCT/tUS98/00623 0 Q MS (+)FAB Wle 298 Treatment of the free base with ethereal HCI gave a white solid (90.0 mp 244-246 MS (+)FAB mWe 298 Elemental analysis for C17H19N302-1.0 HCl*1.7 Calc'd: C, 56.17; H, 6.46; N, 11.56 Found: C, 55.94; H, 6.05; N, 11.42.

Example 3 Benzylamino-et hoxy)- 1 methyl di hyd ro-benzoi mi dazol -2one To a solution of N-benzyl-[2-(2-oxo- 1 3-dihydro-benzoimidazol-4-yloxy)-ethyl

I-

carbamic acid tert-butyl ester in anhydrous methylene chloride (7 mL) was added trifluoracetic acid (3 mL). After 15 min the reaction was poured into aqueous saturated sodium bicarbonate (150 mL) and extracted with mcthylene chloride (2 x 150 mL). The organic layer dried and the solvent removed to afford 170 mg (87 a white solid: mp 137-138'C; MS FAB 298 The fumnarate salt was prepared by adding a solution of the free base (165 mg) in warm isopropanol (15 mL) to an excess of fumaric acid in warm isopropanol (20 mL). Upon completion of addition crystals began forming and the mixture was allowed to cool to room temperature and the crystals filtered to afford 203 mg of fumnarate salt, mp 201.5-202.5 MS ESI mle 298 Elemental analysis for Cl7Hl9N302-C4-1404 Calc'd: C, 61.01; H, 5.61; N, 10.16 Found: C, 60.73; H, 5.36; N, 9.95 Example 4 4 Ben zyl ami n o -pro poxy).-1, 3-d ih y dro- ben zoi m id azol 2 -on e Following the general procedure used in example 1 and using N-benzyl-2,2,2trifluoro-N- [3-(2-oxo-2,3-dihydro- 1H-benzoimidazol-4-yloxy)-propyl] -acetamide. afforded the title compound as a light yellow solid foam (90.4 MS EL Wle 297 Treatment of the free base with ethereal HC1 gave the hydrochloride salt as a white solid (63.9 mp 243-244 MS El mWe 297 22 -1-1-711 IIIIM 17 ,rm-'Ths~Y"7 WO 98/35946 WO 9835946PCTIUS98/00623 Elemental analysis for C17H19N302 -HCl: Calc'd: C, 61.17; H, 6.04; N, 12.59 Found: C, 60.92; H, 5.95; N, 12.41 Example 4-{2-[(Naphthalen-1-ylnlethyl)-anhino]-ethoxy}-1,3-dihydroberizoiinidazol-2-one Following the general procedure used in example 1 and using 2,2,2-trifluoro-Nnaphthalen- 1 -ylmethyl-N- (2-oxo-2,3-dihydro- 1 H- benzoimnidazol -4-yloxy) -ethyl] acetamide (5d) gave the title compound as a white solid (67.4 MS El mle 333 Elemental analysis for C20H1I9N302: Calc'd: C, 72.05; H, 5.74; N, 12.60 Found: C, 71.72; H, 5.76; N, 12.22 Treatment of the free base with ethereal HCl gave the quarter hydrate of the HCl as a white solid (63.9 mp 223-225 MS El Wle 333 Elemental analysis for C17H1I9N302 HCI quarter hydrate: Calc'd: C, 64.17; H, 5.52; N, 11.23 Found: C, 64.33; H, 5.42; N, 11.28 Example 6 4- (4 -te rt-B utyl -benzyla mi no)- ethoxy 1,3-di hyd ro- benzoi mi dazol -2.one Following the general procedure used in example 1 and using N-(4-tert-butylbenzyl)-2,2,2-trifluoro-N-[2-(2-oxo-2,3-dihydro- IH-benzoimidazol-4-yloxy)-ethyl] acetamide gave the title as a white solid (84.5 MS El mle 339 Elemental analysis for C20H25N302: Calc'd: C, 70.77; H, 7.42; N, 12.38 Found: C, 70.59; H, 7.44; N, 12.28 23 WO 98/35946 WO 985946PTIUS98/00623 Treatment of the title compound with ethereal HCl gave the hemnihydrated HCl salt as a white solid, mp 224-226 MS El mWe 339 Elemental analysis for C20H25N302 -HCl hemihydrate: Calc'd: C, 62.41; H, 7.07; N, 10.92 Found: C, 62.64; H, 6.93; N, 10.88 Example 7 4-( 2 [(Thiophen-2-yimethyl)-aminoI-ethoxy}. 1,3-dihydro..benzoimidazoI.

2-one Following the general procedure used in example I and using 2,2,2-trifluor'o-N-[2- (2-oxo-2,3-dihydro- I H -benzoimidazol yloxy) -ethyl thiophen- 2- ylmeth yV-ace tamide the title compound is obtained as a white solid (76.8 MS El nile 289 Elemental analysis for C1I4H1I5N302S: Calc'd: C, 56.36; H, 5.41; N, 14.08 Found: C, 56.42; H, 5.04; N, 14.21 Conversion of the free base to the HCl salt with ethereal gave a white solid, mp 240-241 MIS El mWe 289 Elemental analysis for C141-15N302S HCL: Calc'd: C, 51.61; H, 4.95; N, 12.90 Found: C, 51.22; H, 4.82; N, 12.70 Example 8 4-[2-(4-Chloro-benzylamino)-ethoxy]- 1 ,3-di hydro-benzoimidazol-2-one Following the general procedure used in example 1 and using N-(4-chloro-benzyl)- 2,2,2-trifluoro-N-[2-.(2-oxo-2,3-dihydro- 1 H-benzoimidazol-4-yloxy)-ethyl]-acetaxnide the title compound is obtained as a white solid (77.6 mp 163-164 MIS (+)FAB Wle 3 18/320 Elemental analysis for C16H116C1N302: 24 N In- 4

.'I

WO 98/35946 WO 9835946PCT/US98/00623 Calc'd: C, 60.48; H, 5.08; N, 13.22 Found: C, 60.17; H, 4.83; N, 13.20 Treatment of the free base with ethereal HCl yields the hydrochloride as a white solid, mnp >250 MS El Wle 317/319 Elemental analysis for C1I6H1I6CIN302 HCL: Calc'd: C, 54.25; H, 4.84; N, 11.86 Found: C, 54.18; H, 4.76; N, 11.87 Example 9 4-(2-Benzylamino-ethoxy)-6-chloro- 1 ,3-di hydro-benzoimidazol-2-one Following the general procedure used in example 1 and using N-(4-chloro-benzyl)- 2,2,2- trifluoro-N- (6-c hloro- 2-oxo- 2,3 -dih ydro- I H -ben zo imidazol -4-y Iox y)-ethyl]1acetamide (Lb) afforded the title compound as a white solid (77.6 mp 192-193 MS El mle 317/3 19 Elemental analysis for Cl6Hl16CIN3O2: Calc'd: C, 60.48; H, 5.08; N, 13.22 Found: C, 60.24; H, 5.01; N, 13.09 Treatment of the free base with ethereal HCl gave the hydrochloride salt as a white solid, mp >250 MS El mle 3 17/319 Elemental analysis for CI1H16CIN302. 1 HCL Calc'd: C, 54.25; H, 4.84; N, 11.86 Found: C, 54.23; H, 4.85; N, 11.69 -777'" WO 98/35946 PCT/US98/00623 Example 6 -Chloro-4-{2-[(thiophen-2-ymethyl)-amino]-ethoxy-1,3-dihydrobenzoimidazol-2-one Following the general procedure used in example 1 and using N-[2-(6-chloro-2oxo-2,3-dihydro-lH-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2ylmethyl-acetamide (5i) afforded the title compound as a white solid (89.0 mp 179-180 MS El mle 323/325 Elemental analysis for C14H14CIN302S: Calc'd: C, 51.93; H, 4.36; N, 12.98 Found: C, 51.80; H, 4.23; N, 12.96 Treatment of the title compound with ethereal HCI gave the hydrochloride as a white solid(90.0 mp >250 MS El mle 323/325 Elemental analysis for C14H I4CIN302S HCl: Calc'd: C, 46.68; H, 4.20; N, 11.66 Found: C, 46.52; H, 4.00; N, 11.57 Example 11 6-Chloro-4-{2-[(thiophen-3-ylmethyl)-amino]-ethoxy}-1,3-dihydrobenzoimidazol-2-one Following the general procedure used in example 1 and using N-[2-(6-chloro-2oxo-2,3-dihydro- 1H-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3ylmethyl-acetamide the title compound is obtained as a white solid (89.0 mp 182- 183 MS (+)FAB mle 324/326 Elemental analysis for C14HI4CIN302S: Calc'd: C, 51.93; H, 4.36; N, 12.98 Found: C, 51.96; H, 4.30; N, 12.95 The title compound was treated with ethereal HCI to obtain the hydrochloride salt as a white solid (90.0% mp >250 MS El mle 323/325 26 i pi r~mx~v,<er-. WO 98/35946 PCT/US98/00623 Elemental analysis for C14H14CIN302S HCI: Calc'd: C, 46.68; H, 4.20; N, 11.66 Found: C, 46.29; H, 4.09; N, 11.51 Example 12 4-[2-(2,3-Dihydro-1H-isoquinolin-2yl)-ethoxy]-1,3-dihydrobenzoimidazol-2-one Following the general procedure used in example 1 and using 2-[2-(3,4-dihydro- 1H-isoquinolin-2-yl)-ethoxy]-6-nitro-phenylamine (2k) afforded the title compound as a white solid (63.0 mp 173-174 MS El mle 309 Elemental analysis for C18H19N302: Calc'd: C, 69.88; H, 6.19; N, 13.58 Found: C, 69.48; H, 6.01; N, 13.55 Treatment of the free base with ethereal HC1 gave a quarter hydrate of the hydrochloride salt as a white solid (90.0% mp >250 MS El mle 323/325 Elemental analysis for C 18

H

19

N

3 0 2 HCI 0.25 H 2 0: Calc'd: C, 61.71; H, 5.90; N, 11.99 Found: C, 61.90; H, 5.88; N, 11.97 Example 13 4-[2-(3-Phenyl-propylamine)-ethoxy]-1,3-dihydro-benzoimidazol-2-one Following the general procedures used in intermediates 4 and 5 and example 1, N- [2-(2-amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-(3-phenyl-propyl)-acetamide (3k) afforded the title comound as a white solid; MS (+)FAB mle 312 (M+H Elemental analysis for C 18

H

2 1

N

3 0 2 *0.5 H 2 0: Calc'd: C, 67.48; H, 6.92; N, 13.12 Found: C, 67.81; H, 6.76; N, 13.51 27 WO 98/35946 PCT/US98/00623 Treatment of the free base with ethereal HCI gave the hydrochloride salt as a white solid mp 243-245 MS (+)FAB mle 312 Elemental analysis for C 18

H

21

N

3 0 2 'HCl: Calc'd: C, 62.15; H, 6.38; N, 12.08 Found: C, 62.06; H, 6.21; N, 11.97 Pharmacology A method for determining intrinsic activity at the dopamine D2 receptor was recently reported [Lahti et al., Mol. Pharm., 42, 432-438, (1993)1. 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.

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.

The results of the tests with compounds representative of this invention are given in the immediately following table 28 It -i ii'lF- I- F- -r r-

:?T

WO 98/35946 WO 9835946PCTIUS98/00623 Example IC50 (nM) IC50 (nM) Raio D2 Quin. D2 Spiper 1 0.51 60.6 118 2 0.29 28.5 98 3 2.92 1346 461 4 125.8 5979 47.5 0.60 38.7 64.5 6 0.81 47.8 59 7 0.51 254.6 499.2 8 0.30 99.5 331.7 9 0.48 34.6 70.6 0.47 58.0 123.4 11 0.31 67.0 216.1 12 12.0 657.5 13 0.30 30.0 100.0 Pharmaceutical Composition Compounds of this invention may be administered neat or with a pharmaceutical carrier to a patient in need thereof. The pharmaceutical carrier may be solid or liquid.

Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating 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 n 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 a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity 29 WO 98/35946 PCT/US98/00623 regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferable sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, 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 be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection.

Sterile solutions can also be administered intravenously. Oral administration may be as either a liquid or a solid dosage form.

The compounds of this invention may be administered rectally in the form of a conventinal suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention may be formulated into an aqueous or partrially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semi-solid emulsions of either the oil in water or water in oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to realease the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.

The dosage to be used in the treatment of a specific patient suffering a dopamine imbalance must be subjectively determined by the attending physician. The variables involved include the severity of the dysfunction, and the size, age, and response pattern of the patient.

Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached. Precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated and standerd madical principles.

WO 98/35946 PCT/US98/00623 Preferably the pharmaceutical composition is in unit dosage form, 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 form can be packaged compositions, for example packed 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.

'A I

Claims (28)

1. A compound having the formula Ht-- NR2 NR 3 wherein: R' is hydrogen or CI-C 6 alkyl; 0::to R'is selected from hydrogen. straight-chain and branched C 1 -Cloalkyl. cyclohexylmethyl or -(CI1 2 .)mAr where Ar is phenyl. naphthyi. thicnyl. furainyl or pyridinyl. cach optionally substituted by onc or two substituents ::selected independently from C,-C 6 alkyl, halogen. C,-C 6 alkoxy and or NR'R 2 is 1. 2, 3. 4-tetrahydroquinolin-l-yl or 1. 2, 3. 4-tetrahydroisoxjuinolin- m is n is I or 2; R :2R 3 is hydrogen or alkyl; or0 Y is halogen, C I-C 6 alkyl, C I-C6 alkoxy and hydrogen pharmaceutically acceptable salt thereof.

2. A compound according to claim I which is 4-(2-bcnzvlamino-ethioxy)-lI.3-dihydro- benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 which is 4-[2-(4.methyl-bcnzylamino)-ethoxyl-1,3- di hydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

4. A compound according to claim I which is 4(7)-(2-bcnzylamino-cthoxy)- I-(3)-nlethVI- 1,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof. A compound according to claim I which is 4-(3-benzylamino-propoxy)- l,3-dihydro- benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

A F 32 WO 98/35946 PCT/US98/00623

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

7. A compound according to claim 1 which is 4-[2-(4-tert-butyl-benzylamino)-ethoxy]- 1,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 which is 4-(2-[(thiophen-2-ylmethyl)-amino]- ethoxy)-1,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof. to

9. A compound according to claim 1 which is 4-[2-(4-chloro-benzylamino)-ethoxy]-1,3- dihydro-benzoimidazol-2-oneor a pharmaceutically acceptable salt thereof.

A compound according to claim 1 which is 4-(2-benzylamino-ethoxy)-6-chloro-1,3- dihydro-benzoimidazol-2-oneor a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1 which is 6-Chloro-4-(2-((thiophen-2-ylmethyl)- amino]-ethoxy)- 1,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

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

13. A compound according to claim 1 which is 4-[2-(2,3-Dihydro-IH-isoquinolin-2yl)- ethoxy]-1,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.

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

15. A method of treating diseases in a mammal which respond to treatment by administration of a dopamine D 2 agonist which comprises administration to a mammal in need thereof of a therapeutically effective amount of a compound according to the formula 33 C- 4V: H n R2 H NN wherein: R' is hydrogen or C|-C 6 alkyl; R is selected from hydrogen, straight-chain and branched C|-Clo alkyl, cyclohcxylmcthyl or -(CH,)mAr where Ar is phenyl, naphthyl. thicnyl, furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from alkyl, halogen, alkoxide and trifluoromcthyl; 10 or NR'R' is 1, 2. 3 4-tetrahydroquinolin-l-yl or 1. 2, 3. 4-tetrahvdroisoquinolin- 2-yl; m is n is I or 2; R' is hydrogen or alkyl; Y is halogen, CI-C 6 alkyl, C -C 6 alkoxy and hydrogen or a pharmaceutically acceptable salt thereof.

Sschizophrenia.

17. The method of treatment according to claim 15 wherein the disease treated is Parkinson's disease.

18. The method of treatment according to claim 15 wherein the disease treated is Tourette's syndrome.

19. The method of treatment according to claim 15 wherein the disease treated is alcohol or drug addiction. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to the formula 34 z -r I R' H N 0 I n .".R2 0)l_ NIIN 3 wherein: R' is hydrogen or CI-C 6 alkyl; RI is selected from hydrogen, straight-chain and branched CI -CI(Ialkyl. cyclohexylmethyl or -(Cl 1 2 )mAr where Ar is phenyl. naphthyl. thienyl. furanyl or pyridinyl, each optionally substituted by one or two substitucnts selected independently from C. 1 alkyl, halogen. CI-C, alkoxy and trifluoromethyl; 0 or NR'R 2 is 1, 2, 3, 4-tetrahydroquinolin-I -yl or 1, 4.rctrahdrolscKjuinolln- is2-yl:. n is I or 2; R' is hydrogen or C,-C, 6 alkyl; Y is halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and hydrogen or a pharmaceutically acceptable salt thereof.

I _C

21. A compound as claimed in any one of claims 1 to 14 for use as a medicament.

22. Use of a compound as claimed in any one of claims 1 to 14 for the manufacture of a medicament for treating diseases in a mammal which respond to treatment by administration of a dopamine D 2 agonist.

23. A use according to claim 22 wherein the disease treated is schizophrenia.

24. A use according to claim 22 wherein the disease treated is Parkinson's disease.

A use according to claim 22 wherein the disease treated is Tourette's syndrome.

26. A use according to claim 22 wherein the disease treated is alcohol or drug S addiction.

27. A compound according to claim 1 substantially as hereinbefore described with 6* reference to any of the examples.

28., A method according to claim 15 substantially as hereinbefore described. "5 DATED: 19 July 2001 PHILLIPS ORMONDE FITZPATRICK Attorneys for: AMERICAN HOME PRODUCTS CORPORATION a4 a C W'.VROADGAY-NOOELETE'595749 1