CA2278747A1 - 4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-one derivatives, their preparation and their use as dopamine autoreceptor (d2) agonists - Google Patents
4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-one derivatives, their preparation and their use as dopamine autoreceptor (d2) agonists Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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Abstract
Disclosed are compounds of formula (I), wherein R1 is hydrogen or C1-C6 alkyl; R2 is selected from hydrogen, straight-chain and branched C1-C10 alkyl, cyclohexylmethyl or -(CH2)mAr where Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from C1-C6 alkyl, halogen, C1-C6 alkoxy and trifluoromethyl; or NR1R2 is 1,2,3,4-tetrahydroquinolin-1-yl or 1,2,3,4-tetrahydroisoquinolin-2-yl; m is 1-5; n is 1 or 2; R3 is hydrogen or C1-C6 alkyl; Y is halogen, C1-C6 alkyl, and C1-C6 alkoxy; or a pharmaceutically acceptable salt thereof, which are dopamine autoreceptor agonists and as such are useful in the treatment of schizophrenia, Parkinson's disease, Tourette's syndrome, alcohol addiction and drug addiction.
Description
4-AMINOALKOXY-1,3-DIHYDROBENZOIMIDAZOL-2-0NE 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, to 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 (i.e, activate only autoreceptors versus postsynaptic D2 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).
2o 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 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 2s 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, i.e., as full agonists. As such, they are useful in the treatment of diseases having abnormal concentrations of dopamine 3o could be used as dopamine surrogates such as schizophrenia, Parkinson's disease and Tourette's syndrome. Such agents are partial agonists at the postsynaptic dopamine D2 receptor and are thereby useful in the treatment of alcohol and drug addiction.
In the Belgian patent 850,166, Ciba-Geigy discloses compounds represented by the compound of the formula below which have both a and (3-adrenergic properties and are 35 useful as cardiovascular and antihypertensive agents.
WO 98/35946 PG"f/US98/00623 -HN \ I O~~t Bu a- NH OH
O
Summary of the Invention Compounds of this invention are 4-aminoalkoxy-1,3-dihydro-benzoimidazol-2-s ones which are illustrated by Formula I below HEN \ I o~N~R2 ~N~
O
to I
wherein:
R' is hydrogen or C1-C6 alkyl;
RZ is selected from hydrogen, straight-chain and branched C1-Cto alkyl, cyclohexylmethyl or -(CH2)mAr where Ar is phenyl, naphthyl, thienyl, 1 s furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from C,-C6 alkyl, halogen, C,-C6 alkoxide and trifluoromethyl;
or NR'RZ is 1, 2, 3, 4-tetrahydroquinolin-1-yl or 1, 2, 3, 4-tetrahydroisoquinolin-2-yl;
2o m is 1-5;
nis 1 or2;
R3 is hydrogen or C,-C6 alkyl;
Y is halogen, C,-C6 alkyl, and C,-C6 alkoxy;
and the pharmaceutically acceptable salts thereof.
25 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 3o serve to modulate the synthesis and release of the neurotranmitter dopamine. They are thus useful for treatment of disorders of the dopaminergic system, such as schizophrenia, Parkinson's disease and Tourette's syndrome. Such agents are partial agonists at the postsynaptic dopamine DZ receptor and are thereby useful in the treatment of alcohol and drug addiction.
s Detailed Description of the Invention The compounds of Formula I are generally prepared by the overall sequence depicted in Schemes I -N. When one or both of R' and R2 is hydrogen, it is desirable to protect the basic nitrogen with a suitable protecting group such as the trifluoroacetyl group t o or t-butyloxycarbonyl group. Scheme I outlines a procedure to prepare an invention compound where R3 is H.
Scheme I
is H O~C~
/ NH2 / NH2 "O~N~Ri -~ I ~ / NH2 trifluorwnW c N02 \ N02 ~ ~ NO anhydndc 1 fn=1or21 O'\ /CF3 O~CF3 O~n~~R~ HZNNHz O~/~N'~R1 cm / NH2 lo% Pa/c / NH2 or NOp Raney Nickel ~ NH2 ethanol O'\'CF3 H
O~'~IN~R1 O
n H 1. IC2C03 N O MeOH/H20 / N
HCI salt N~ 2. Hct ~ ( O
H
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, to 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 (i.e, activate only autoreceptors versus postsynaptic D2 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).
2o 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 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 2s 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, i.e., as full agonists. As such, they are useful in the treatment of diseases having abnormal concentrations of dopamine 3o could be used as dopamine surrogates such as schizophrenia, Parkinson's disease and Tourette's syndrome. Such agents are partial agonists at the postsynaptic dopamine D2 receptor and are thereby useful in the treatment of alcohol and drug addiction.
In the Belgian patent 850,166, Ciba-Geigy discloses compounds represented by the compound of the formula below which have both a and (3-adrenergic properties and are 35 useful as cardiovascular and antihypertensive agents.
WO 98/35946 PG"f/US98/00623 -HN \ I O~~t Bu a- NH OH
O
Summary of the Invention Compounds of this invention are 4-aminoalkoxy-1,3-dihydro-benzoimidazol-2-s ones which are illustrated by Formula I below HEN \ I o~N~R2 ~N~
O
to I
wherein:
R' is hydrogen or C1-C6 alkyl;
RZ is selected from hydrogen, straight-chain and branched C1-Cto alkyl, cyclohexylmethyl or -(CH2)mAr where Ar is phenyl, naphthyl, thienyl, 1 s furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from C,-C6 alkyl, halogen, C,-C6 alkoxide and trifluoromethyl;
or NR'RZ is 1, 2, 3, 4-tetrahydroquinolin-1-yl or 1, 2, 3, 4-tetrahydroisoquinolin-2-yl;
2o m is 1-5;
nis 1 or2;
R3 is hydrogen or C,-C6 alkyl;
Y is halogen, C,-C6 alkyl, and C,-C6 alkoxy;
and the pharmaceutically acceptable salts thereof.
25 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 3o serve to modulate the synthesis and release of the neurotranmitter dopamine. They are thus useful for treatment of disorders of the dopaminergic system, such as schizophrenia, Parkinson's disease and Tourette's syndrome. Such agents are partial agonists at the postsynaptic dopamine DZ receptor and are thereby useful in the treatment of alcohol and drug addiction.
s Detailed Description of the Invention The compounds of Formula I are generally prepared by the overall sequence depicted in Schemes I -N. When one or both of R' and R2 is hydrogen, it is desirable to protect the basic nitrogen with a suitable protecting group such as the trifluoroacetyl group t o or t-butyloxycarbonyl group. Scheme I outlines a procedure to prepare an invention compound where R3 is H.
Scheme I
is H O~C~
/ NH2 / NH2 "O~N~Ri -~ I ~ / NH2 trifluorwnW c N02 \ N02 ~ ~ NO anhydndc 1 fn=1or21 O'\ /CF3 O~CF3 O~n~~R~ HZNNHz O~/~N'~R1 cm / NH2 lo% Pa/c / NH2 or NOp Raney Nickel ~ NH2 ethanol O'\'CF3 H
O~'~IN~R1 O
n H 1. IC2C03 N O MeOH/H20 / N
HCI salt N~ 2. Hct ~ ( O
H
Scheme II shows a synthetic route for invention compounds where R3 is not H.
Scheme II
s O\ /CF3 O \ /CF3 ~N NN' 1 O~n ~RZ trifluoroacetic O~n ~R
NH2 anhydride / NHCOCF3 DMSO
\ N02 \ ~ NO
O'\ /CF3 H
O~N~Ri O~N~R1 NR3COCFg KzCOs / NHR3 BoczO
\ , NO Me o \ ~ N02 Z $
~oc ~oc O~nN~Rt O~N~R1 --~ ~ -.-\ I N02 Pd/C \ ~ NH
L
to ~oc ~oc R~ N~O R3 Rte ~,~0 R3 N 1. ~A N
O 2. Hct ~ ~ ~O
a H H
Scheme III shows a synthetic route for invention compounds where neither of R' and RZ is H.
Scheme II
s O\ /CF3 O \ /CF3 ~N NN' 1 O~n ~RZ trifluoroacetic O~n ~R
NH2 anhydride / NHCOCF3 DMSO
\ N02 \ ~ NO
O'\ /CF3 H
O~N~Ri O~N~R1 NR3COCFg KzCOs / NHR3 BoczO
\ , NO Me o \ ~ N02 Z $
~oc ~oc O~nN~Rt O~N~R1 --~ ~ -.-\ I N02 Pd/C \ ~ NH
L
to ~oc ~oc R~ N~O R3 Rte ~,~0 R3 N 1. ~A N
O 2. Hct ~ ~ ~O
a H H
Scheme III shows a synthetic route for invention compounds where neither of R' and RZ is H.
Scheme III
\ \
' N I / N
O~n O~n NOZ lo~ ~ I NH2 Hct ethanol 2k a N
O~n H
/ N
HCI salt N
H
Scheme IV shows the procedure used to prepare an intermediate where Y is Cl.
Scheme IV
Io O~C~ O~CI
/ NH2 NCS ~ / NH2 \ ~ N02 CH3CN C \ ~ NOp ZZ
The following specific examples illustrate the synthetic procedures for the ~ 5 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.
\ \
' N I / N
O~n O~n NOZ lo~ ~ I NH2 Hct ethanol 2k a N
O~n H
/ N
HCI salt N
H
Scheme IV shows the procedure used to prepare an intermediate where Y is Cl.
Scheme IV
Io O~C~ O~CI
/ NH2 NCS ~ / NH2 \ ~ N02 CH3CN C \ ~ NOp ZZ
The following specific examples illustrate the synthetic procedures for the ~ 5 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.
Intermediate 1 a 2-(2-Chloro-ethoxy)-6-vitro-phenylamine s Method 1.
To a solution of 2-amino-3-nitrophenol (5.0 g, 32.4 mmol)) triphenylphosphine (12.8 g, 48.7 mmol) and 2-chloroethanol (3.9 g, 48.7 mmol) in tetrahydrofuran (120 mL) at 0 - 5° C was added over 30 min a solution of diethyl azodicarboxylate (8.5 g) 48.7 1 o rnlnol) in tetrahydrofuran (75 mL). The mixture was warmed to 2'~°
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 (44.2%) of an orange solid, mp 71-73 °C; MS (+)PBEI mle 216/218 (M').
t s 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 2s 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 (84.6%) of product as an orange solid, ~mp 71-73 °C; MS (+)PBEI
mle 216/218 (M+).
Intermediate 1 b 2-(3-Bromo-propoxy)-6-vitro-phenylamine Following the procedure of method 2 above, and using 1,3-dibromopropane, the title compound was as a yellow solid, (78.7%) mp 88-89 °C; MS EI mle 274/276 (M+).
3s 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 Intermediate 2a 2-(2-Benzylamino-ethoxy)-6-vitro-phenylamine s A mixture of 2-(2-chloro-ethoxy)-6-vitro-phenylamine (1~, 3.0 g, 13.8 mmol) and benzylamine (9.0 g, 84.0 mmol) was heated neat at 100-110° 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 t o 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').
1 s Elemental analysis for C 1 SH 17N303:
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 2o Using this general procedure and utilizing 2-(2-chloro-ethoxy)-6-vitro-phenylamine or 2-(3-bromo-propoxy)-6-vitro-phenylamine or 4-chloro-2-(2-chloro-ethoxy)-6-nitro phenylamine and 4-methyl-benzylamine, 1-naphthalene-methylamine, 4-tert-butyl benzylamine, thiophene-2-methyl-amine, 4-chloro-bcnzylamine, thiophene-3-methyl amine, 1,2,3,4-tetrahydroisoquinoline or 3-phenyl-1-propylamine produced the following 2s intermediates Zb-21, respectively:
2h 2-[2-(4-Methyl-benzylamino)-ethoxy]-6-vitro-phenylamine as a yellow solid (89 %), mp 55-57 °C; EI mle 301 (M').
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-vitro-phenylamine as a viscous orange oil ss (85.5 %); MS EI mle 301 (M').
Elemental analysis for C16H19N303:
Calc'd: C, 63.77; H, 6.36; N, 13.94 Found: C, 63.66; H, 6.28; N, 13.89 s 2~i 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').
Elemental analysis for C19H19N3~3:
Calc'd: C, 67.64; H, 5.68; N, 12.45 Found: C, 67.20; H, 5.66; N, 12.26 l0 2~ 2-[2-(4-tent-Butylbenzylamino)-ethoxy]-6-vitro-phenylamine as an orange viscous oil (83.3 %); MS EI mle 343 (M').
Elemental analysis for C19H25N3~3 ' 0.25 H20:
Calc'd: C, 65.59; H, 7.39; N, 12.07 1 s Found: C, 65.89; H, 7.20; N, 11.94 2f 2-Nitro-6-{2--[(thiophen-2-ylmethyl)-amino]-ethoxy}-phenylamine as a red semi-solid material (88.5%); MS EI mle 389 (M').
2o Elemental analysis for C13H15N3~3S~
Calc'd: C, 53.23; H, 5.15; N, 14.32 Found: C, 52.86; H, 4.93; N, 14.1 S
2-[2-(4-Chloro-benzylamino)-ethoxy]-6-vitro-phenylamine as an orange 2s solid (87.8 %), mp 61-62 °C; MS EI mle 322/324 (M~).
Elemental analysis for C15H16N3~3 ' 0.25 H20:
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-vitro-phenylamine as a orange-brown colored solid (54.0 %), mp 87-88 °C; MS EI mle 321/323 (M+).
Elemental analysis for C15H16CIN303:
3s Calc'd: C, 55.99; H, 5.01; N, 13.06 Found: C, 55.85; H, 4.90; N, 13.13 2i 4-Chloro-2-nitro-6- f 2-[(thiophen-2-ylmethyl)-amino]-ethoxy}-phenylamine as a yellow solid (44.0 %), mp 74-75 °C; MS EI mle 327/329 (M'") Elemental analysis for C13H14C1N302S:
s Calc'd: C, 47.67; H, 4.33; N, 12.75 Found: C, 47.54; H, 4.11; N, 13.06 io 2i 4-Chloro-2-vitro-6-{2-[(thiophen-3-ylmethyl)-amino]-ethoxy}-phenylamine as a yellow solid (33.3 %), mp 77-78 °C; MS EI mle 327/329 (M').
Elemental analysis for C13H14C1N302S:
Calc'd: C) 47.67; H, 4.33; N) 12.75 Found: C, 47.54; H, 4.18; N) 12.80 is ~k_ 2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethoxy]-6-vitro-phenylamine as a yellow solid (87.1 %), mp 95-97 °C; MS EI mle 313 (M+).
Elemental analysis for C17H19N302:
Calc'd: C, 65.16; H, 6.11; N, 13.41 2o Found: C, 64.87; H, 6.11; N, 13.40 21 2-Nitro-6--[2-(-phenyl-propylamino)-ethoxy]-phenylamine as a viscous orange oil (83.9%); MS EI mle 315 (M').
2s Elemental analysis for C,~HZ1N303~0.25 H20:
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-vitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide To a solution of 2-(2-benzylamino-ethoxy)-6-vitro-phenylamine (2,~, 0.5 g, 1.74 mmol) and triethylamine (0.32 mL) 3.48 mmol) in anhydrous methylene chloride (10 mL) 3s at 23° 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 organic layer dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave 0.55 g (81.7%) of yellow solid, mp 134-135 °C; MS EI mle 383 (M+).
Elemental analysis for C17H16F3N304:
s 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-[2-(4-methyl-benzylamino)-ethoxy]-6-vitro-phenylamine, 2-(3-benzylamino-propoxy)-6-vitro-phenylamine, 2- ( 2-[(naphthalen-l0 1-ylmethyl)-amino]-ethoxy}-6-vitro-phenylamine, 2-[2-(4-tert-butylbenzylamino)-ethoxy]-6-vitro-phenyl-amine, 2-vitro-6- { 2-[(thiophen-2-ylmethyl)-amino]-ethoxy } -phenylamine, 2-[2-(4-chloro-benzylamino)-ethoxy]-6-vitro-phenylamine, 2-(2-benzylamino-ethoxy)-4-chloro-6-vitro-phenylamine) 4-chloro-2-vitro-6-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy}-phenylamine, 4-chloro-2-vitro-6-{2-[(thiophen-3-ylmethyl)-amino}-ethoxy}-1 s phenylamine and 2-nitro-6-[ 2-(3-phenyl-propylamino)-ethoxy]-phenylamine gave respectively:
3b N-[2-(2-Amino-3-vitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-(4-methyl-benzyl) acetamide as a yellow solid (79 %), mp 172-173 °C; MS EI mlc 397 (M').
Elemental analysis for C1gH18F3N304;
Calc'd: C, 54.41; H, 4.57; N, 10.58 Found: C, 54.34; H, 4.33; N, 10.53 2s 3c N-[3-(2-Amino-3-vitro-phenoxy)-propyl]-N-benzyl-2,2,2-trifluoro-acetamide as a yellow solid (67.8 %), mp 92-93 °C; MS EI mle 397 (M+).
Elemental analysis for C18H18F3N304;
Calc'd: C, 54.41; H, 4.57; N, 10.58 3o Found: C, 54.30; H, 4.50; N, 10.50 N-[2-(2-Amino-3-vitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-naphthalen-1-ylmethyl-acetamide as a yellow-orange colored solid (75.3 %), mp 133-135 °C; MS EI mle 433 (Mi).
Elemental analysis for C21H18F3N304:
Calc'd: C, 58.20; H, 4.19; N, 9.70 Found: C, 58.28; H, 4.07; N, 9.48 N-[2-(2-Amino-3-vitro-phenoxy)-ethyl]-N-(4-tert-butyl-benzyl)-2,2,2-trifluoro-acetamide as a yellow solid (82.0 %), mp 80-82 °C; MS
EI mle 439 s (M+).
Elemental analysis for C21H24F3N3~4:
Calc'd: C) 57.40; H, 5.51; N, 9.56 Found: C, 57.09; H) 5.31; N, 9.40 to ~f N-[2-(2-Amino-3-vitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide as a yellow solid (77.4 %), mp 143-144 °C; MS EI
mle 389 (M').
Elemental analysis for C15H14F3N3~4S:
i s Calc'd: C, 46.27; H, 3.62; N, 10.79 Found: C, 46.19; H, 3.39; N, 10.64 N-[2-(2-Amino-3-vitro-phenoxy)-ethyl]-N-(4-chloro-benzyl)-2,2,2-trifluoro-acetamide as a yellow solid (84.0 %), mp 138-139 °C; MS
(+)FAB mle 20 418/420 (M+H+) Elemental analysis for C17H15C1F3N304:
Calc'd: C, 48.88; H, 3.62; N, 10.06 Found: C, 48.66; H, 3.47; N, 9.82 N-[2-(2-Amino-5-chloro-3-vitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide as a yellow solid (67.9 %), mp 106-108 °C; MS
(+)FAB mle 418/420 (M+H+).
3o 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 N-[2-(2-Amino-5-chloro-3-vitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-ss thiophen-2-ylmethyl-acetamide as a yellow solid (59.6 %), mp 97-98 °C; MS EI mle 423/425 (M+).
Elemental analysis for C15H13C1F3N304S:
Calc'd: C, 42.51; H, 3.09; N, 9.92 Found: C, 42.37; H, 2.97; N, 9.84 s ~ N-[2-(2-Amino-5-chloro-3-vitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide as a yellow solid (80.0 %), mp 149-150 °C; MS EI
mle 423/425 (Ma).
Elemental analysis for C15H13C1F3N304S:
to Calc'd: C, 42.51; H, 3.09; N, 9.92 Found: C, 42.02; H, 2.95; N, 9.78 ~c N-[2-(2-amino-3-vitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-(3-phenyl-propyl)-acetamide as a yellow solid (72.6%), mp 81-82 °C; MS EI mle 411 (M').
is Elemental analysis for C19H20F3N3~4~
Calc'd: C, 55.47; H, 4.90; N, 10.21 Found: C, 55.57; H, 4.66; N, 10.23 2o Intermediate 4a N-Benzyl-N-f2-12.3-diamino-~henoxvl-ethvll-2.2.2-trifluoro-acetamide To a mixture of N-[2-(2-amino-3-vitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-2s acetamide (,~, 2.4 g, 6.26 mmol) and 10 % palladium on carbon (0.40 g) in ethanol (200 mL) at 50-55°C was added a solution of hydrazine hydrate (2.0 g) in ethanol (25 mL). The reaction was allowed to stir for 18 hr at 23°C, then the catalyst filtered through solka floc and the solvent removed under vacuum to afford 1.96 g (88.9 %) of an amber-colored oil.
Crystallization from ethyl acetate - hexane gave a white solid, mp 118 -119 °C; MS
30 (+)FAB mle 354 (M+H+).
Elemental analysis for C17H18F3N302:
Calc'd: C, 56.58; H, 4.72; N, 12.38 Found: C, 57.49; H, 5.10; N, 11.86 3s Following the above procedure and utilizing N-[2-(2-amino-3-vitro-phenoxy)-ethyl)-2,2,2-trifluoro-N-(4-methyl-benzyl) acetamide, N-[3-(2-amino-3-vitro-phenoxy)-propyl]-N-benzyl-2,2,2-trifluoro-acetamide, N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-naphthalen-1-ylmethyl-acetamide, N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-N-(4-tert-butyl-benzyl)-2,2,2-trifluoro-acetamide, N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide, N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-N-(4-s 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-acetamide, and N-[2-(2-amino-5-chloro-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide afforded respectively:
to 4~! N-[2-(2,3-Diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-(4-methyl-benzyl)-acetamide as a white solid (85.0 %), mp 94-96 °C; MS EI mle 367 (M').
Elemental analysis for C 1 gH2pF3N302:
i s Calc'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)-propyl]-2,2,2-trifluoro-acetamide as a white solid (86.5 %), mp 56-58 °C; MS EI mle 367 (M').
Elemental analysis for C18H2pF3N302:
Calc'd: C, 58.85; H, 5.49; N, 11.44 Found: C, 59.00; H, 5.42; N, 11.48 2s 4~ N-[2-(2,3-Diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-naphthalen-1-ylmethyl-acetamide as a viscous yellow oil (63.0 %); MS (+)FAB mle 404 (M+H').
Elemental analysis for C21H20F3N3~2:
Calc'd: C) 62.53; H, 5.00; N, 10.42 3o Found: C, 62.45; H, 4.98; N, 10.20 4~ N-(4-tert-Butyl-benzyl)-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-acetamide as a viscous brown oil (72.7 %); MS EI mle 409 (M+).
ss 4f N-[2-(2,3-Diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-Z-ylmethyl-acetamide as a white solid (41.0 %), mp 72-74 °C; MS (+)FAB
mle 404 (M+H+).
Elemental analysis for C15H16F3N3~2S:
Calc'd: C, 50.13; H, 4.49; N, 11.69 Found: C, 50.09; H, 4.38; N, 11.59 s 4g N-(4-Chloro-benzyl)-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-acetarnide as a brown oil (80.9 %); MS EI mle 387/389 (M+).
Elemental analysis for C17H17C1F3N302:
t o Calc'd: C, 52.65; H, 4.42; N, 10.84 Found: C, 52.47; H, 4.51; N, 10.60 4h N-Benzyl-N-[2-(2,3-diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-acetamide as a viscous brown oil (76.2 %); MS EI mle 387/389 (M+).
is Elemental analysis for C17H17C1F3N302:
Calc'd: C, 52.65; H, 4.42; N, 10.84 Found: C, 52.47; H, 4.39; N, 10.90 20 4i N-[2-(2,3-Diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide as a viscous brown oil (71.4 %); MS EI mle 393/395 (M+).
Elemental analysis for C15H15C1F3N302S:
2s Calc'd: C, 45.75; H, 3.84; N, 10.67 Found: C, 45.58; H, 3.93; N, 10.64 41 N-[2-(2,3-Diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide as a viscous brown oil (75.0 %); MS EI mle 30 393/395 (M+).
Elemental analysis for C15H15C1F3N302S:
Calc'd: C, 45.75; H, 3.84; N, 10.67 Found: C, 45.39; H, 3.84; N, 10.56 Intermediate 5a N-Benzyl-2,2,2-trifluoro-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4 yloxy)-ethyl]-acetamide A mixture of N-benzyl-N-[2-(2,3-diamino-phenoxy)-ethyl]-2.2,2-trifluoro-acetamide (0.28 g, 0.804 mmol) and diimidazole carbonyl (0.326 g, 2.0 mrnol) in anhydrous tetrahydrofuran (10 mL) was stirred at 23° C for 2 hr. 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 under vacuum.
to Purification by chromatography (60 g silica gel, ethyl acetate : hexane : 2 M NH3 in methanol (15 : 5 : 1)) afforded 0.29 g (94.8%) of a colorless oil.
Crystallization from hexane gave a white solid, mp 121-123 °C; MS EI mle 379 (M').
Elemental analysis for CI8H16F3N303;
1s Calc'd: C, 56.99; H, 4.25; N) 11.08 Found: C, 57.09; H, 4.U7; N, 11.10.
Utilizing N-[2-(2,3-diamino-phenoxy)-ethyl)-2,2,2-trifluoro-N-(4-methyl-benzyl)-acetamide, N-benzyl-N-[3-(2,3-diamino-phenoxy)-propyl]-2,2,2-trif7uoro-acetamide, N-20 [2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-naphthalen-1-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-(4-chloro-benzyl)-N-(2-(2,3-diamino-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-(2,3-2s diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide and N-[2-(2,3-diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide in the above general procedure afforded respectively:
5,~ 2,2,2-Trifluoro-N-(4-methyl-benzyl)-N-[2-(2-oxo-2,3-dihydro-1H-3o benzoimidazol-4-yloxy)-ethyl]-acetamide ~ 0.1 ethyl acetate as a white solid (96.6 %)) mp 194-196 °C; MS (+)FAB mle 394 (M+H+).
Elemental analysis for C19H18F3N303 ~ 0.1 C4H802 Calc'd: C, 57.94; H, 4.71; N, 10.45 3s Found: C, 57.90; H, 4.60; N, 10.19 ~c N-Benzyl-2,2,2-trifluoro-N-[3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propyl]-acetamide as a white solid (86.0 %), mp 114-116 °C; MS (+)FAB mle 394 (M+H+).
Elemental analysis for C19H18F3N3U3 Calc'd: C, 58.01; H, 4.61; N, 10.68 Found: C, 57.67; H, 4.37; N, 10.49 5~ 2,2,2-Trifluoro-N-naphthalen-1-ylmethyl-N-[2-(2-oxo-2,3-dihydro-to 1 H-benzoimidazol-4-yloxy)-ethyl]-acetamide as a white solid (90.0 %), mp °C; MS EI mle 429 (M+).
Elemental analysis for C22H18F3N303 Calc'd: C, 61.54; H, 4.23; N, 9.79 is Found: C, 61.34; H, 4.25; N, 9.52 Se N-(4-tert-Butyl-benzyl)-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 °C; MS EI mle 435 (M+).
Elemental analysis for C22H24F3N3~3 Calc'd: C, 60.68; H, 5.55; N, 9.65 Found: C, 60.59; H, 5.55; N, 9.66 2s Sf 2,2,2-Trifluoro-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-N-thiophen-2-ylmethyl-acetamide as a white solid (73.3 %), mp 49-50 °C; MS EI mle 385 (M+).
5g N-(4-Chloro-benzyl)-2,2,2-trifluoro-N-[2-(2-oxo-2,3-dihydro-1H-so benzoimidazol-4-yloxy)-ethyl]-acetamide as a white solid (56.7 %), mp 190-°C; MS (+)FAB mle 414/416 (M+H+).
Elemental analysis for C18H15C1F3N303 Calc'd: C, 52.25; H, 3.65; N, 10.16 ss Found: C, 52.28; H, 3.55; N, 10.20 ~h_ N-Benzyl-N-[2-(6-chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-acetamide as a white solid (60.0 %), mp 171-173 °C;
MS (+)APCI mle 414.2/416.2 (M+H+).
s Elemental analysis for C18H15C1F3N303 Calc'd: C, 52.25; H, 3.65; N, 10.16 Found: C, 52.10; H, 3.56; N, 9.96 N-[2~(6-Chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-lo ethyl]- 2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide as a white solid (70.1 %), mp 153-154 °C; MS EI mle 419/421 (M+).
Elemental analysis for C16H13C1F3N303S:
Calc'd: C, 45.78; H, 3.12; N, 10.01 is Found: C, 45.85; H) 3.02; N) 9.73 5~' N-[2-(6-Chloro-2-oxo-2,3-dihydro-1 f1-benzoimidazol-4-yloxy)-ethyl]- 2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide as a white solid (77.8 %), mp 152-153 °C; MS EI mle 419/421 (M+).
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 N-[2-(2-{2,2,2-Trifluoroacetamidyl}-3-nitro-phenoxy)-ethyl]-N-benzyl 2,2,2-trifluoro-acetamide To a suspension of N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide (4.95 g, 12.9 mmol) 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) 3s and the organic layer dried over anhydrous magnesium sulfate. Upon filtration and evaporation of the solvent gave 5.84 g (94.4%) of yellowish white solid, mp 114-115 °C;
MS FAB mle 480 (M+H+).
Elemental analysis for C19H15F6N3~5 Calc'd: C, 47.61; H, 3.15; N, 8.77 Found: C, 47.35; H, 2.94; N, 8.69 s Intermediate 7 N-[2-(1-Methyl-2-{2,2,2-Trifluoroacetamidyl}-3-nitro-phenoxy)-ethyl]-N-lo benzyt-2,2,2-trifluoro-acetamide A suspension of potassium carbonate (1.44g, 10.4 mmoll. h-[2-(2-{2,2,2-trifluoroacetanudyl}-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-aretamide ( 1.0 g) 2.09 mmol) and methyl iodide (2.96 g, 20.9 mmol, previously fihered through basic t s alumina) in anhydrous dimethylsulfoxide ( 11 mL) was allowed to stir at room temperature for 24 h. The reaction mixture was poured into methylene chloride (2()n mL) 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 2o yellow solid, mp 90-92.5 °C; MS mle EI 493 (M+).
Elemental analysis for C2pH17F6N305 Calc'd: C, 48.70; H, 3.47; N, 8.57 Found: C, 48.50; H, 3.27; N, 8.39 Intermediate 8 N-Benzyl-2-(2-methylamino-3-nitro-phenoxy)-ethylamine A suspension of potassium carbonate (2.52 g, 18.2 mmol) and N-[2-1-methyl-(2-{ 2,2,2-trifluoroacetamidyl } -3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide (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 3s 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 by passing through a short pad of silica to afford 505 mg (92.1 %) of N-benzyl-(methylamino-3-vitro-phenoxy)ethylamine as a red oil; MS FAB mle 302 (M+H+).
Intermediate 9 s N-Benzyl-[2-(2- methylamino-3-vitro-phenoxy)-ethyl]-carbamic acid tert butyl ester A solution of N-benzyl-2-(2-methylamino-3-nitro-phenoxy)-ethylamine to (480 mg, 1.59 mmol) and di-tert-butyl Bicarbonate (348 mg, 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 mL). The organic layer dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated to afford 593 mg (93 %) of an orange solid, mp 91-93 °C; MS mle EI 401 (M').
is Elemental analysis for C21H27N30$
Calc'd: C, 62.83; H, 6.78; N) 10.47 Found: C) 62.78; H) 6.53; N, 10.51 Intermediate 10 2s N-Benzyl-[2-(2-methylamino-3-amino-phenoxy)-ethyl]-carbamic acid tert butyl ester To a mixture of N-benzyl-[2-(2-methylamino-3-vitro-phenoxy)-ethyl)-carbamic acid tent-butyl ester (520 mg, 1.30 mmol) and ~ 10 % palladium on carbon ( 120 mg) in ethanol (40 mL) at 50 °C was added a solution of hydrazine hydrate ( 1.3 g) in ethanol ( 10 mL). The reaction was allowed to stir for 3 hr then the catalyst filtered through celite and so the solvent removed. Purification by chromatography (30 % ethyl acetate-hexane) afforded 380 mg (78.9 %) of a clear oil; MS EI mle 371 (M'); IR (film) 3400, 3350, 1680 cm-1.
Intermediate 11 N-Benzyl-[2-(2-oxo-1,3-dihydro-benzoimidazol-4-yloxy)-ethyl]-carbamic acid tert-butyl ester s A mixture of N-benzyl-[2-(2-methylamino-3-amino-phenoxy)-ethyl]-carbamic acid tent-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 1 o 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 (M+H+); IR (KBr) 3420) 3250) 1690 (bs) cm-1.
is Intermediate 12 3-(2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethoxy]-benzene-1,2-diamine 2o The general procedure used in intermediate 4 using 2-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-ethoxy]-6-nitro-phenylamine (2k} afforded 3-[2-(3,4-dihydro-isoquinolin-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 EI mle 283 (M+).
2s Elemental analysis for C17H21N30 ~ 2 HCl ~ 0.4 H20:
Calc'd: C, 56.17; H, 6.6U; N, 11.56 Found: C, 56.15; H, 6.68; N, 11.25 3o Intermediate 13 4-Chloro-2-(2-chloro-ethoxy)-6-vitro-phenylamine A solution of 2-(2-chloro-ethoxy)-6-vitro-phenylamine ( la, 30.0 g, 0.14 mol), N-ss 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.Sg (95.3 %) as orange solid, mp 109-110 °C; MS EI mle 250/252/254 (M+).
s 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 1 o 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-2,2,2-ts trifluoro-N-[2-(2-oxo-1,3-dihydro-IH-benzoimidazol-4-yloxy)-ethylj-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 20 132-135°C. Without further purification, this material was dissolved in ethyl acetate-methanol (1:1) and treated with an excess amount of 1 N HCl in ether to afford 0.30g (75.0%) of the hydrochloride salt as a light tan-colored solid, mp 230-233 °C: MS EI mle 283 (M+).
2s Elemental analysis for C 16H 17N302~HC1 Calc'd: C, 60.09; H, 5.67; N, 13.14 Found: C, 59.84; H, 5.59; N, 12.92 3o Example 2 4-[2-(4-Methyl-benzylamino)-ethoxy]-I,3-dihydro-benzoimidazol-2-one Following the general procedure used in example 1 and utilizing 2,2,2-trifluoro-N-3s (4-methyl-benzyl)-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamide ~ 0.1 ethyl acetate (Sb) afforded the title compound as a white solid (64.5 %
), mp 162-163 °C; MS (+)FAB mle 298 (M+H+). Treatment of the free base with ethereal HCI gave a white solid (90.0 %), mp 244-246 °C: MS (+)FAB mle 298 (M+H+).
Elemental analysis for C17H19N302~1.0 HCl~1.7 H20 s Calc'd: C, 56.17; H, 6.46; N, 11.56 Found: C, 55.94; H, 6.05; N, 11.42.
Example 3 to 4(7)-(2-Benzylamino-ethoxy)-1-(3)-methyl-1,3-dihydro-benzoimidazol-2-one To a solution of N-benzyl-[2-(2-oxo-1,3-dihydro-benzoimidazol-4-yloxy)-ethyl ]-t s 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 methylene chloride (2 x 150 mL). The organic layer dried and the solvent removed to afford I70 mg (87 %) a white solid: mp 137-138°C; MS FAB 298 (M+H+). The fumarate salt was prepared by adding a solution 20 of the free base ( 165 mg) in warm isopropanol ( 1 S 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 fumarate salt, mp 201.5-202.5 °C; MS ESI mle 298 (M+H').
2s Elemental analysis for C17HI9N302~C~04 Calc'd: C, 61.01; H, 5.61; N, 10.16 Found: C, 60.73; H, 5.36; N, 9.95 so Example 4 4-(3-Benzylamino-propoxy)-1,3-dihydro-benzoimidazol-2-one Following the general procedure used in example 1 and using N-benzyl-2,2,2-s5 trifluoro-N-[3-(2-oxo-2,3-dihydro- 1H-benzoimidazol-4-yloxy)-propyl]-acetamide (Sc) afforded the title compound as a light yellow solid foam (90.4 %}; MS EI mle 297 (M+).
Treatment of the free base with ethereal HCI gave the hydrochloride salt as a white solid (63.9 %), mp 243-244 °C: MS EI mle 297 (M+).
Elemental analysis for C17H19N302 ~ HCI:
Calc'd: C, 61.17; H, 6.04; N, 12.59 Found: C, 60.92; H, 5.95; N, 12.41 s Example 5 4-{Z-[(Naphthalen-1-ylmethyl)-amino]-ethoxy}-1,3-dihydro benzoimidazol-2-one to Following the general procedure used in example 1 and using 2,2,2-trifluoro-N-naphthalen-1-ylmethyl-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamide (Sd) gave the title compound as a white solid (67.4 %); MS EI mle 333 (M+).
is Elemental analysis for C2pH1gN302:
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 2o solid (63.9 %), mp 223-225 °C: MS EI mle 333 (M+).
Elemental analysis for C 17H 19N302 ~ HCl ~ 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-[2-(4-tent-Butyl-benzylamino)-ethoxy]-1,3-dihydro-benzoimidazo!-2-one Following the general procedure used in example 1 and using N-(4-tert-butyi-benzyl)-2,2,2-trifluoro-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamide (35g) gave the title as a white solid (84.5 %); MS EI mle 339 (M+).
3s Elemental analysis for C2pH25N3~2:
Calc'd: C, 70.77; H, 7.42; N, 12.38 Found: C, 70.59; H, 7.44; N, 12.28 Treatment of the title compound with ethereal HCI gave the hemihydrated HCl salt as a white solid, mp 224-226 °C: MS EI mle 339 (M+).
Elemental analysis for C2pH25N3~2 ' HCl ~ hemihydrate:
s Calc'd: C, 62.41; H, 7.07; N, 10.92 Found: C, 62.64; H, 6.93; N, 10.88 Example 7 to 4-{2-[(Thiophen-2-ylmethyl)-amino]-ethoxy}-1,3-dihydro-benzoimidazol 2-one Following the general procedure used in example 1 and using 2,2,2-trifluoro-N-[2-ts (2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl)-N-thiophen-2-ylmethyl-acetamide SUf , the title compound is obtained as a white solid (76.8 %); MS EI mle 289 (M+).
Elemental analysis for C14H15N3~2S:
Calc'd: C, 56.36; H, 5.41; N, 14.08 2o 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 °C: MS EI mle 289 (M+).
2s Elemental analysis for C1qH15N3~2S ~ HCI:
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-dihydro-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]-acetamide 3s (~}, the title compound is obtained as a white solid (77.6 %), mp 163-164 °C; MS
(+)FAB mle 318/320 (M+H+).
Elemental analysis for C16H16C1N302:
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, mp s >250 °C: MS EI mle 317/319 (M+).
Elemental analysis for C16H16C1N302 ~ HCI:
Calc'd: C, 54.25; H, 4.84; N) 11.86 Found: C, 54.18; H, 4.76; N, 11.87 to Example 9 4-(2-Benzylamino-ethoxy)-6-chloro-1,3-dihydro-benzoimidazol-2-one is Following the general procedure used in example 1 and using N-(4-chloro-benzyl)-2,2,2-trifluoro-N-[2-(6-chloro-2-oxo-2,3-dihydro-1 H-benzoimidazol-4-yloxy)-ethyl]-acetamide {5h) afforded the title compound as a white solid (77.6 %), mp 192-193 °C; MS
EI mle 317/319 (M+).
Elemental analysis for C16H16C1N302:
Calc'd: C, 60.48; H, 5.08; N, 13.22 Found: C, 60.24; H, 5.01; N, 13.09 2s Treatment of the free base with ethereal HCI gave the hydrochloride salt as a white solid, mp >250 °C: MS EI mle 317/319 (M+).
Elemental analysis for C16H16C1N302 ~ 1HC1:
Calc'd: C, 54.25; H, 4.84; N, 11.86 so Found: C, 54.23; H, 4.85; N, 11.69 Example 10 6-Chloro-4-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy~-1,3-dihydro benzoimidazol-2-one s to Following the general procedure used in example 1 and using N-[2-(6-chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-yimethyl-acetamide ~) afforded the title compound as a white solid (89.0 %), mp 179-180 °C; MS EI mle 323/325 (M+).
Elemental analysis for C14H14C1N302S:
Calc'd: C, 51.93; H, 4.36; N, 12.98 Found: C, 51.80; H, 4.23; N, 12.96 i s Treatment of the title compound with ethereal HCI gave the hydrochloride as a white solid(90.0 %), mp >250 °C: 1VIS EI mle 323/325 (M+).
Elemental analysis for C14H14C1N302S ~ HCI:
Calc'd: C, 46.68; H, 4.20; N, 11.66 2o Found: C, 46.52; H, 4.00; N, 11.57 Example 11 6-Chloro-4-{2-[(thiophen-3-ylmethyl)-amino]-ethoxy}-1,3-dihydro-2s benzoimidazol-2-one Following the general procedure used in. example 1 and using N-[2-(6-chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylinethyl-acetamide (~), the title compound is obtained as a white solid (89.0 %), mp 182-30 183 °C; MS (+)FAB mle 324/326 (M+H+).
Elemental analysis for C14H14C1N302S:
Calc'd: C, 51.93; H, 4.36; N, 12.98 Found: C, 51.96; H, 4.30; N, 12.95 3s 'The title compound was treated with ethereal HC1 to obtain the hydrochloride salt as a white solid (90.0% ), mp, >250 °C: MS EI mle 323/325 (M+).
Elemental analysis~for C14H14C1N302S ~ 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-2y1)-ethoxy]-1,3-dihydro-to benzoimidazol-2-one Following the general procedure used in example 1 and using 2-[2-(3,4-dihydro-1 H-isoquinolin-2-yl)-ethoxy)-6-vitro-phenylamine (~ afforded the title compound as a white solid (63.0 %)) mp 173-174 °C; MS EI mle 309 (M+).
is Elemental analysis for C 18H 19N302:
Calc'd: C, 69.88; H, 6.19; N, 13.58 Found: C) 69.48; H, 6.01; N, 13.55 2o Treatment of the free base with ethereal HCl gave a quarter hydrate of the hydrochloride salt as a white solid (90.0% ), mp >250 °C: MS EI mle 323/325 (M+).
Elemental analysis for C18H19N3O2 ~ HCl ~ 0.25 H20:
Calc'd: C, 61.71; H, 5.90; N, 11.99 2s Found: C, 61.90; H, 5.88; N, 11.97 Example 13 4-[2-(3-Phenyl-propylamine)-ethoxy]-1,3-dihydro-benzoimidazol-2-one so Following the general procedures used in intermediates 4 and 5 and example 1, N-[2-(2-amino-3-vitro-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 C1gH21N3O2~O.S HZO:
ss Calc'd: C, 67.48; H, 6.92; N, 13.12 Found: C, 67.81; H, 6.76; N, 13.51 Treatment of the free base with ethereal HCl gave the hydrochloride salt as a white solid (90.9%), mp 243-245 °C; MS (+)FAB mle 312 (M+H+).
Elemental analysis for C18H2tN30z~HCI:
s 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 t o 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.
1 s 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 3H-quinpiroie (Quin.) and various concentrations of test compound, filtered and washed and counted in a Betaplate scintillation counter.
2o High affinity for the dopamine D-2 receptor was established by the standard experimental test procedure of Fields, et al., Brain Res., 1 ~6, 578 ( 1977) and Yamamura et al., eds., Neurotransmitter Receptor Binding, Raven Press, N.Y. (1978) wherein homogenized limbic brain tissue is incubated with -~H-spiroperidol (Spiper.) and various concentrations of test compound, filtered and washed and shaken with Hydrofluor 2s scintillation cocktail (National Diagnostics) and counted in a Packard 460 ~ scintillation counter.
The results of the tests with compounds representative of this invention are given in the immediately following table Example ICSO (nM) ICgO
# D2 Quin. (nM) 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 55 13 0.30 30.0 100.(1 Pharmaceutical Composition s 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 i o 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, 1 s 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 2o 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 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, e.g., glycols) and their s 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 1 o 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 ~ 5 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 rransdermal patch containing the active compound and a Garner that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic 2o 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 2s devices may be used to realease the active ingredient into the blood stream such as a semipernleable 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 3o 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 ss 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.
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 form can be packaged compositions, for example packed powders) vials) ampoules, prefilled syringes or sachets containing liquids.
s 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.
To a solution of 2-amino-3-nitrophenol (5.0 g, 32.4 mmol)) triphenylphosphine (12.8 g, 48.7 mmol) and 2-chloroethanol (3.9 g, 48.7 mmol) in tetrahydrofuran (120 mL) at 0 - 5° C was added over 30 min a solution of diethyl azodicarboxylate (8.5 g) 48.7 1 o rnlnol) in tetrahydrofuran (75 mL). The mixture was warmed to 2'~°
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 (44.2%) of an orange solid, mp 71-73 °C; MS (+)PBEI mle 216/218 (M').
t s 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 2s 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 (84.6%) of product as an orange solid, ~mp 71-73 °C; MS (+)PBEI
mle 216/218 (M+).
Intermediate 1 b 2-(3-Bromo-propoxy)-6-vitro-phenylamine Following the procedure of method 2 above, and using 1,3-dibromopropane, the title compound was as a yellow solid, (78.7%) mp 88-89 °C; MS EI mle 274/276 (M+).
3s 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 Intermediate 2a 2-(2-Benzylamino-ethoxy)-6-vitro-phenylamine s A mixture of 2-(2-chloro-ethoxy)-6-vitro-phenylamine (1~, 3.0 g, 13.8 mmol) and benzylamine (9.0 g, 84.0 mmol) was heated neat at 100-110° 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 t o 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').
1 s Elemental analysis for C 1 SH 17N303:
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 2o Using this general procedure and utilizing 2-(2-chloro-ethoxy)-6-vitro-phenylamine or 2-(3-bromo-propoxy)-6-vitro-phenylamine or 4-chloro-2-(2-chloro-ethoxy)-6-nitro phenylamine and 4-methyl-benzylamine, 1-naphthalene-methylamine, 4-tert-butyl benzylamine, thiophene-2-methyl-amine, 4-chloro-bcnzylamine, thiophene-3-methyl amine, 1,2,3,4-tetrahydroisoquinoline or 3-phenyl-1-propylamine produced the following 2s intermediates Zb-21, respectively:
2h 2-[2-(4-Methyl-benzylamino)-ethoxy]-6-vitro-phenylamine as a yellow solid (89 %), mp 55-57 °C; EI mle 301 (M').
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-vitro-phenylamine as a viscous orange oil ss (85.5 %); MS EI mle 301 (M').
Elemental analysis for C16H19N303:
Calc'd: C, 63.77; H, 6.36; N, 13.94 Found: C, 63.66; H, 6.28; N, 13.89 s 2~i 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').
Elemental analysis for C19H19N3~3:
Calc'd: C, 67.64; H, 5.68; N, 12.45 Found: C, 67.20; H, 5.66; N, 12.26 l0 2~ 2-[2-(4-tent-Butylbenzylamino)-ethoxy]-6-vitro-phenylamine as an orange viscous oil (83.3 %); MS EI mle 343 (M').
Elemental analysis for C19H25N3~3 ' 0.25 H20:
Calc'd: C, 65.59; H, 7.39; N, 12.07 1 s Found: C, 65.89; H, 7.20; N, 11.94 2f 2-Nitro-6-{2--[(thiophen-2-ylmethyl)-amino]-ethoxy}-phenylamine as a red semi-solid material (88.5%); MS EI mle 389 (M').
2o Elemental analysis for C13H15N3~3S~
Calc'd: C, 53.23; H, 5.15; N, 14.32 Found: C, 52.86; H, 4.93; N, 14.1 S
2-[2-(4-Chloro-benzylamino)-ethoxy]-6-vitro-phenylamine as an orange 2s solid (87.8 %), mp 61-62 °C; MS EI mle 322/324 (M~).
Elemental analysis for C15H16N3~3 ' 0.25 H20:
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-vitro-phenylamine as a orange-brown colored solid (54.0 %), mp 87-88 °C; MS EI mle 321/323 (M+).
Elemental analysis for C15H16CIN303:
3s Calc'd: C, 55.99; H, 5.01; N, 13.06 Found: C, 55.85; H, 4.90; N, 13.13 2i 4-Chloro-2-nitro-6- f 2-[(thiophen-2-ylmethyl)-amino]-ethoxy}-phenylamine as a yellow solid (44.0 %), mp 74-75 °C; MS EI mle 327/329 (M'") Elemental analysis for C13H14C1N302S:
s Calc'd: C, 47.67; H, 4.33; N, 12.75 Found: C, 47.54; H, 4.11; N, 13.06 io 2i 4-Chloro-2-vitro-6-{2-[(thiophen-3-ylmethyl)-amino]-ethoxy}-phenylamine as a yellow solid (33.3 %), mp 77-78 °C; MS EI mle 327/329 (M').
Elemental analysis for C13H14C1N302S:
Calc'd: C) 47.67; H, 4.33; N) 12.75 Found: C, 47.54; H, 4.18; N) 12.80 is ~k_ 2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethoxy]-6-vitro-phenylamine as a yellow solid (87.1 %), mp 95-97 °C; MS EI mle 313 (M+).
Elemental analysis for C17H19N302:
Calc'd: C, 65.16; H, 6.11; N, 13.41 2o Found: C, 64.87; H, 6.11; N, 13.40 21 2-Nitro-6--[2-(-phenyl-propylamino)-ethoxy]-phenylamine as a viscous orange oil (83.9%); MS EI mle 315 (M').
2s Elemental analysis for C,~HZ1N303~0.25 H20:
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-vitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide To a solution of 2-(2-benzylamino-ethoxy)-6-vitro-phenylamine (2,~, 0.5 g, 1.74 mmol) and triethylamine (0.32 mL) 3.48 mmol) in anhydrous methylene chloride (10 mL) 3s at 23° 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 organic layer dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave 0.55 g (81.7%) of yellow solid, mp 134-135 °C; MS EI mle 383 (M+).
Elemental analysis for C17H16F3N304:
s 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-[2-(4-methyl-benzylamino)-ethoxy]-6-vitro-phenylamine, 2-(3-benzylamino-propoxy)-6-vitro-phenylamine, 2- ( 2-[(naphthalen-l0 1-ylmethyl)-amino]-ethoxy}-6-vitro-phenylamine, 2-[2-(4-tert-butylbenzylamino)-ethoxy]-6-vitro-phenyl-amine, 2-vitro-6- { 2-[(thiophen-2-ylmethyl)-amino]-ethoxy } -phenylamine, 2-[2-(4-chloro-benzylamino)-ethoxy]-6-vitro-phenylamine, 2-(2-benzylamino-ethoxy)-4-chloro-6-vitro-phenylamine) 4-chloro-2-vitro-6-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy}-phenylamine, 4-chloro-2-vitro-6-{2-[(thiophen-3-ylmethyl)-amino}-ethoxy}-1 s phenylamine and 2-nitro-6-[ 2-(3-phenyl-propylamino)-ethoxy]-phenylamine gave respectively:
3b N-[2-(2-Amino-3-vitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-(4-methyl-benzyl) acetamide as a yellow solid (79 %), mp 172-173 °C; MS EI mlc 397 (M').
Elemental analysis for C1gH18F3N304;
Calc'd: C, 54.41; H, 4.57; N, 10.58 Found: C, 54.34; H, 4.33; N, 10.53 2s 3c N-[3-(2-Amino-3-vitro-phenoxy)-propyl]-N-benzyl-2,2,2-trifluoro-acetamide as a yellow solid (67.8 %), mp 92-93 °C; MS EI mle 397 (M+).
Elemental analysis for C18H18F3N304;
Calc'd: C, 54.41; H, 4.57; N, 10.58 3o Found: C, 54.30; H, 4.50; N, 10.50 N-[2-(2-Amino-3-vitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-naphthalen-1-ylmethyl-acetamide as a yellow-orange colored solid (75.3 %), mp 133-135 °C; MS EI mle 433 (Mi).
Elemental analysis for C21H18F3N304:
Calc'd: C, 58.20; H, 4.19; N, 9.70 Found: C, 58.28; H, 4.07; N, 9.48 N-[2-(2-Amino-3-vitro-phenoxy)-ethyl]-N-(4-tert-butyl-benzyl)-2,2,2-trifluoro-acetamide as a yellow solid (82.0 %), mp 80-82 °C; MS
EI mle 439 s (M+).
Elemental analysis for C21H24F3N3~4:
Calc'd: C) 57.40; H, 5.51; N, 9.56 Found: C, 57.09; H) 5.31; N, 9.40 to ~f N-[2-(2-Amino-3-vitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide as a yellow solid (77.4 %), mp 143-144 °C; MS EI
mle 389 (M').
Elemental analysis for C15H14F3N3~4S:
i s Calc'd: C, 46.27; H, 3.62; N, 10.79 Found: C, 46.19; H, 3.39; N, 10.64 N-[2-(2-Amino-3-vitro-phenoxy)-ethyl]-N-(4-chloro-benzyl)-2,2,2-trifluoro-acetamide as a yellow solid (84.0 %), mp 138-139 °C; MS
(+)FAB mle 20 418/420 (M+H+) Elemental analysis for C17H15C1F3N304:
Calc'd: C, 48.88; H, 3.62; N, 10.06 Found: C, 48.66; H, 3.47; N, 9.82 N-[2-(2-Amino-5-chloro-3-vitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide as a yellow solid (67.9 %), mp 106-108 °C; MS
(+)FAB mle 418/420 (M+H+).
3o 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 N-[2-(2-Amino-5-chloro-3-vitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-ss thiophen-2-ylmethyl-acetamide as a yellow solid (59.6 %), mp 97-98 °C; MS EI mle 423/425 (M+).
Elemental analysis for C15H13C1F3N304S:
Calc'd: C, 42.51; H, 3.09; N, 9.92 Found: C, 42.37; H, 2.97; N, 9.84 s ~ N-[2-(2-Amino-5-chloro-3-vitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide as a yellow solid (80.0 %), mp 149-150 °C; MS EI
mle 423/425 (Ma).
Elemental analysis for C15H13C1F3N304S:
to Calc'd: C, 42.51; H, 3.09; N, 9.92 Found: C, 42.02; H, 2.95; N, 9.78 ~c N-[2-(2-amino-3-vitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-(3-phenyl-propyl)-acetamide as a yellow solid (72.6%), mp 81-82 °C; MS EI mle 411 (M').
is Elemental analysis for C19H20F3N3~4~
Calc'd: C, 55.47; H, 4.90; N, 10.21 Found: C, 55.57; H, 4.66; N, 10.23 2o Intermediate 4a N-Benzyl-N-f2-12.3-diamino-~henoxvl-ethvll-2.2.2-trifluoro-acetamide To a mixture of N-[2-(2-amino-3-vitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-2s acetamide (,~, 2.4 g, 6.26 mmol) and 10 % palladium on carbon (0.40 g) in ethanol (200 mL) at 50-55°C was added a solution of hydrazine hydrate (2.0 g) in ethanol (25 mL). The reaction was allowed to stir for 18 hr at 23°C, then the catalyst filtered through solka floc and the solvent removed under vacuum to afford 1.96 g (88.9 %) of an amber-colored oil.
Crystallization from ethyl acetate - hexane gave a white solid, mp 118 -119 °C; MS
30 (+)FAB mle 354 (M+H+).
Elemental analysis for C17H18F3N302:
Calc'd: C, 56.58; H, 4.72; N, 12.38 Found: C, 57.49; H, 5.10; N, 11.86 3s Following the above procedure and utilizing N-[2-(2-amino-3-vitro-phenoxy)-ethyl)-2,2,2-trifluoro-N-(4-methyl-benzyl) acetamide, N-[3-(2-amino-3-vitro-phenoxy)-propyl]-N-benzyl-2,2,2-trifluoro-acetamide, N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-naphthalen-1-ylmethyl-acetamide, N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-N-(4-tert-butyl-benzyl)-2,2,2-trifluoro-acetamide, N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide, N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-N-(4-s 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-acetamide, and N-[2-(2-amino-5-chloro-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide afforded respectively:
to 4~! N-[2-(2,3-Diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-(4-methyl-benzyl)-acetamide as a white solid (85.0 %), mp 94-96 °C; MS EI mle 367 (M').
Elemental analysis for C 1 gH2pF3N302:
i s Calc'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)-propyl]-2,2,2-trifluoro-acetamide as a white solid (86.5 %), mp 56-58 °C; MS EI mle 367 (M').
Elemental analysis for C18H2pF3N302:
Calc'd: C, 58.85; H, 5.49; N, 11.44 Found: C, 59.00; H, 5.42; N, 11.48 2s 4~ N-[2-(2,3-Diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-naphthalen-1-ylmethyl-acetamide as a viscous yellow oil (63.0 %); MS (+)FAB mle 404 (M+H').
Elemental analysis for C21H20F3N3~2:
Calc'd: C) 62.53; H, 5.00; N, 10.42 3o Found: C, 62.45; H, 4.98; N, 10.20 4~ N-(4-tert-Butyl-benzyl)-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-acetamide as a viscous brown oil (72.7 %); MS EI mle 409 (M+).
ss 4f N-[2-(2,3-Diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-Z-ylmethyl-acetamide as a white solid (41.0 %), mp 72-74 °C; MS (+)FAB
mle 404 (M+H+).
Elemental analysis for C15H16F3N3~2S:
Calc'd: C, 50.13; H, 4.49; N, 11.69 Found: C, 50.09; H, 4.38; N, 11.59 s 4g N-(4-Chloro-benzyl)-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-acetarnide as a brown oil (80.9 %); MS EI mle 387/389 (M+).
Elemental analysis for C17H17C1F3N302:
t o Calc'd: C, 52.65; H, 4.42; N, 10.84 Found: C, 52.47; H, 4.51; N, 10.60 4h N-Benzyl-N-[2-(2,3-diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-acetamide as a viscous brown oil (76.2 %); MS EI mle 387/389 (M+).
is Elemental analysis for C17H17C1F3N302:
Calc'd: C, 52.65; H, 4.42; N, 10.84 Found: C, 52.47; H, 4.39; N, 10.90 20 4i N-[2-(2,3-Diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide as a viscous brown oil (71.4 %); MS EI mle 393/395 (M+).
Elemental analysis for C15H15C1F3N302S:
2s Calc'd: C, 45.75; H, 3.84; N, 10.67 Found: C, 45.58; H, 3.93; N, 10.64 41 N-[2-(2,3-Diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide as a viscous brown oil (75.0 %); MS EI mle 30 393/395 (M+).
Elemental analysis for C15H15C1F3N302S:
Calc'd: C, 45.75; H, 3.84; N, 10.67 Found: C, 45.39; H, 3.84; N, 10.56 Intermediate 5a N-Benzyl-2,2,2-trifluoro-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4 yloxy)-ethyl]-acetamide A mixture of N-benzyl-N-[2-(2,3-diamino-phenoxy)-ethyl]-2.2,2-trifluoro-acetamide (0.28 g, 0.804 mmol) and diimidazole carbonyl (0.326 g, 2.0 mrnol) in anhydrous tetrahydrofuran (10 mL) was stirred at 23° C for 2 hr. 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 under vacuum.
to Purification by chromatography (60 g silica gel, ethyl acetate : hexane : 2 M NH3 in methanol (15 : 5 : 1)) afforded 0.29 g (94.8%) of a colorless oil.
Crystallization from hexane gave a white solid, mp 121-123 °C; MS EI mle 379 (M').
Elemental analysis for CI8H16F3N303;
1s Calc'd: C, 56.99; H, 4.25; N) 11.08 Found: C, 57.09; H, 4.U7; N, 11.10.
Utilizing N-[2-(2,3-diamino-phenoxy)-ethyl)-2,2,2-trifluoro-N-(4-methyl-benzyl)-acetamide, N-benzyl-N-[3-(2,3-diamino-phenoxy)-propyl]-2,2,2-trif7uoro-acetamide, N-20 [2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-naphthalen-1-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-(4-chloro-benzyl)-N-(2-(2,3-diamino-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-(2,3-2s diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide and N-[2-(2,3-diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide in the above general procedure afforded respectively:
5,~ 2,2,2-Trifluoro-N-(4-methyl-benzyl)-N-[2-(2-oxo-2,3-dihydro-1H-3o benzoimidazol-4-yloxy)-ethyl]-acetamide ~ 0.1 ethyl acetate as a white solid (96.6 %)) mp 194-196 °C; MS (+)FAB mle 394 (M+H+).
Elemental analysis for C19H18F3N303 ~ 0.1 C4H802 Calc'd: C, 57.94; H, 4.71; N, 10.45 3s Found: C, 57.90; H, 4.60; N, 10.19 ~c N-Benzyl-2,2,2-trifluoro-N-[3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propyl]-acetamide as a white solid (86.0 %), mp 114-116 °C; MS (+)FAB mle 394 (M+H+).
Elemental analysis for C19H18F3N3U3 Calc'd: C, 58.01; H, 4.61; N, 10.68 Found: C, 57.67; H, 4.37; N, 10.49 5~ 2,2,2-Trifluoro-N-naphthalen-1-ylmethyl-N-[2-(2-oxo-2,3-dihydro-to 1 H-benzoimidazol-4-yloxy)-ethyl]-acetamide as a white solid (90.0 %), mp °C; MS EI mle 429 (M+).
Elemental analysis for C22H18F3N303 Calc'd: C, 61.54; H, 4.23; N, 9.79 is Found: C, 61.34; H, 4.25; N, 9.52 Se N-(4-tert-Butyl-benzyl)-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 °C; MS EI mle 435 (M+).
Elemental analysis for C22H24F3N3~3 Calc'd: C, 60.68; H, 5.55; N, 9.65 Found: C, 60.59; H, 5.55; N, 9.66 2s Sf 2,2,2-Trifluoro-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-N-thiophen-2-ylmethyl-acetamide as a white solid (73.3 %), mp 49-50 °C; MS EI mle 385 (M+).
5g N-(4-Chloro-benzyl)-2,2,2-trifluoro-N-[2-(2-oxo-2,3-dihydro-1H-so benzoimidazol-4-yloxy)-ethyl]-acetamide as a white solid (56.7 %), mp 190-°C; MS (+)FAB mle 414/416 (M+H+).
Elemental analysis for C18H15C1F3N303 Calc'd: C, 52.25; H, 3.65; N, 10.16 ss Found: C, 52.28; H, 3.55; N, 10.20 ~h_ N-Benzyl-N-[2-(6-chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-acetamide as a white solid (60.0 %), mp 171-173 °C;
MS (+)APCI mle 414.2/416.2 (M+H+).
s Elemental analysis for C18H15C1F3N303 Calc'd: C, 52.25; H, 3.65; N, 10.16 Found: C, 52.10; H, 3.56; N, 9.96 N-[2~(6-Chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-lo ethyl]- 2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide as a white solid (70.1 %), mp 153-154 °C; MS EI mle 419/421 (M+).
Elemental analysis for C16H13C1F3N303S:
Calc'd: C, 45.78; H, 3.12; N, 10.01 is Found: C, 45.85; H) 3.02; N) 9.73 5~' N-[2-(6-Chloro-2-oxo-2,3-dihydro-1 f1-benzoimidazol-4-yloxy)-ethyl]- 2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide as a white solid (77.8 %), mp 152-153 °C; MS EI mle 419/421 (M+).
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 N-[2-(2-{2,2,2-Trifluoroacetamidyl}-3-nitro-phenoxy)-ethyl]-N-benzyl 2,2,2-trifluoro-acetamide To a suspension of N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide (4.95 g, 12.9 mmol) 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) 3s and the organic layer dried over anhydrous magnesium sulfate. Upon filtration and evaporation of the solvent gave 5.84 g (94.4%) of yellowish white solid, mp 114-115 °C;
MS FAB mle 480 (M+H+).
Elemental analysis for C19H15F6N3~5 Calc'd: C, 47.61; H, 3.15; N, 8.77 Found: C, 47.35; H, 2.94; N, 8.69 s Intermediate 7 N-[2-(1-Methyl-2-{2,2,2-Trifluoroacetamidyl}-3-nitro-phenoxy)-ethyl]-N-lo benzyt-2,2,2-trifluoro-acetamide A suspension of potassium carbonate (1.44g, 10.4 mmoll. h-[2-(2-{2,2,2-trifluoroacetanudyl}-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-aretamide ( 1.0 g) 2.09 mmol) and methyl iodide (2.96 g, 20.9 mmol, previously fihered through basic t s alumina) in anhydrous dimethylsulfoxide ( 11 mL) was allowed to stir at room temperature for 24 h. The reaction mixture was poured into methylene chloride (2()n mL) 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 2o yellow solid, mp 90-92.5 °C; MS mle EI 493 (M+).
Elemental analysis for C2pH17F6N305 Calc'd: C, 48.70; H, 3.47; N, 8.57 Found: C, 48.50; H, 3.27; N, 8.39 Intermediate 8 N-Benzyl-2-(2-methylamino-3-nitro-phenoxy)-ethylamine A suspension of potassium carbonate (2.52 g, 18.2 mmol) and N-[2-1-methyl-(2-{ 2,2,2-trifluoroacetamidyl } -3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide (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 3s 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 by passing through a short pad of silica to afford 505 mg (92.1 %) of N-benzyl-(methylamino-3-vitro-phenoxy)ethylamine as a red oil; MS FAB mle 302 (M+H+).
Intermediate 9 s N-Benzyl-[2-(2- methylamino-3-vitro-phenoxy)-ethyl]-carbamic acid tert butyl ester A solution of N-benzyl-2-(2-methylamino-3-nitro-phenoxy)-ethylamine to (480 mg, 1.59 mmol) and di-tert-butyl Bicarbonate (348 mg, 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 mL). The organic layer dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated to afford 593 mg (93 %) of an orange solid, mp 91-93 °C; MS mle EI 401 (M').
is Elemental analysis for C21H27N30$
Calc'd: C, 62.83; H, 6.78; N) 10.47 Found: C) 62.78; H) 6.53; N, 10.51 Intermediate 10 2s N-Benzyl-[2-(2-methylamino-3-amino-phenoxy)-ethyl]-carbamic acid tert butyl ester To a mixture of N-benzyl-[2-(2-methylamino-3-vitro-phenoxy)-ethyl)-carbamic acid tent-butyl ester (520 mg, 1.30 mmol) and ~ 10 % palladium on carbon ( 120 mg) in ethanol (40 mL) at 50 °C was added a solution of hydrazine hydrate ( 1.3 g) in ethanol ( 10 mL). The reaction was allowed to stir for 3 hr then the catalyst filtered through celite and so the solvent removed. Purification by chromatography (30 % ethyl acetate-hexane) afforded 380 mg (78.9 %) of a clear oil; MS EI mle 371 (M'); IR (film) 3400, 3350, 1680 cm-1.
Intermediate 11 N-Benzyl-[2-(2-oxo-1,3-dihydro-benzoimidazol-4-yloxy)-ethyl]-carbamic acid tert-butyl ester s A mixture of N-benzyl-[2-(2-methylamino-3-amino-phenoxy)-ethyl]-carbamic acid tent-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 1 o 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 (M+H+); IR (KBr) 3420) 3250) 1690 (bs) cm-1.
is Intermediate 12 3-(2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethoxy]-benzene-1,2-diamine 2o The general procedure used in intermediate 4 using 2-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-ethoxy]-6-nitro-phenylamine (2k} afforded 3-[2-(3,4-dihydro-isoquinolin-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 EI mle 283 (M+).
2s Elemental analysis for C17H21N30 ~ 2 HCl ~ 0.4 H20:
Calc'd: C, 56.17; H, 6.6U; N, 11.56 Found: C, 56.15; H, 6.68; N, 11.25 3o Intermediate 13 4-Chloro-2-(2-chloro-ethoxy)-6-vitro-phenylamine A solution of 2-(2-chloro-ethoxy)-6-vitro-phenylamine ( la, 30.0 g, 0.14 mol), N-ss 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.Sg (95.3 %) as orange solid, mp 109-110 °C; MS EI mle 250/252/254 (M+).
s 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 1 o 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-2,2,2-ts trifluoro-N-[2-(2-oxo-1,3-dihydro-IH-benzoimidazol-4-yloxy)-ethylj-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 20 132-135°C. Without further purification, this material was dissolved in ethyl acetate-methanol (1:1) and treated with an excess amount of 1 N HCl in ether to afford 0.30g (75.0%) of the hydrochloride salt as a light tan-colored solid, mp 230-233 °C: MS EI mle 283 (M+).
2s Elemental analysis for C 16H 17N302~HC1 Calc'd: C, 60.09; H, 5.67; N, 13.14 Found: C, 59.84; H, 5.59; N, 12.92 3o Example 2 4-[2-(4-Methyl-benzylamino)-ethoxy]-I,3-dihydro-benzoimidazol-2-one Following the general procedure used in example 1 and utilizing 2,2,2-trifluoro-N-3s (4-methyl-benzyl)-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamide ~ 0.1 ethyl acetate (Sb) afforded the title compound as a white solid (64.5 %
), mp 162-163 °C; MS (+)FAB mle 298 (M+H+). Treatment of the free base with ethereal HCI gave a white solid (90.0 %), mp 244-246 °C: MS (+)FAB mle 298 (M+H+).
Elemental analysis for C17H19N302~1.0 HCl~1.7 H20 s Calc'd: C, 56.17; H, 6.46; N, 11.56 Found: C, 55.94; H, 6.05; N, 11.42.
Example 3 to 4(7)-(2-Benzylamino-ethoxy)-1-(3)-methyl-1,3-dihydro-benzoimidazol-2-one To a solution of N-benzyl-[2-(2-oxo-1,3-dihydro-benzoimidazol-4-yloxy)-ethyl ]-t s 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 methylene chloride (2 x 150 mL). The organic layer dried and the solvent removed to afford I70 mg (87 %) a white solid: mp 137-138°C; MS FAB 298 (M+H+). The fumarate salt was prepared by adding a solution 20 of the free base ( 165 mg) in warm isopropanol ( 1 S 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 fumarate salt, mp 201.5-202.5 °C; MS ESI mle 298 (M+H').
2s Elemental analysis for C17HI9N302~C~04 Calc'd: C, 61.01; H, 5.61; N, 10.16 Found: C, 60.73; H, 5.36; N, 9.95 so Example 4 4-(3-Benzylamino-propoxy)-1,3-dihydro-benzoimidazol-2-one Following the general procedure used in example 1 and using N-benzyl-2,2,2-s5 trifluoro-N-[3-(2-oxo-2,3-dihydro- 1H-benzoimidazol-4-yloxy)-propyl]-acetamide (Sc) afforded the title compound as a light yellow solid foam (90.4 %}; MS EI mle 297 (M+).
Treatment of the free base with ethereal HCI gave the hydrochloride salt as a white solid (63.9 %), mp 243-244 °C: MS EI mle 297 (M+).
Elemental analysis for C17H19N302 ~ HCI:
Calc'd: C, 61.17; H, 6.04; N, 12.59 Found: C, 60.92; H, 5.95; N, 12.41 s Example 5 4-{Z-[(Naphthalen-1-ylmethyl)-amino]-ethoxy}-1,3-dihydro benzoimidazol-2-one to Following the general procedure used in example 1 and using 2,2,2-trifluoro-N-naphthalen-1-ylmethyl-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamide (Sd) gave the title compound as a white solid (67.4 %); MS EI mle 333 (M+).
is Elemental analysis for C2pH1gN302:
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 2o solid (63.9 %), mp 223-225 °C: MS EI mle 333 (M+).
Elemental analysis for C 17H 19N302 ~ HCl ~ 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-[2-(4-tent-Butyl-benzylamino)-ethoxy]-1,3-dihydro-benzoimidazo!-2-one Following the general procedure used in example 1 and using N-(4-tert-butyi-benzyl)-2,2,2-trifluoro-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamide (35g) gave the title as a white solid (84.5 %); MS EI mle 339 (M+).
3s Elemental analysis for C2pH25N3~2:
Calc'd: C, 70.77; H, 7.42; N, 12.38 Found: C, 70.59; H, 7.44; N, 12.28 Treatment of the title compound with ethereal HCI gave the hemihydrated HCl salt as a white solid, mp 224-226 °C: MS EI mle 339 (M+).
Elemental analysis for C2pH25N3~2 ' HCl ~ hemihydrate:
s Calc'd: C, 62.41; H, 7.07; N, 10.92 Found: C, 62.64; H, 6.93; N, 10.88 Example 7 to 4-{2-[(Thiophen-2-ylmethyl)-amino]-ethoxy}-1,3-dihydro-benzoimidazol 2-one Following the general procedure used in example 1 and using 2,2,2-trifluoro-N-[2-ts (2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl)-N-thiophen-2-ylmethyl-acetamide SUf , the title compound is obtained as a white solid (76.8 %); MS EI mle 289 (M+).
Elemental analysis for C14H15N3~2S:
Calc'd: C, 56.36; H, 5.41; N, 14.08 2o 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 °C: MS EI mle 289 (M+).
2s Elemental analysis for C1qH15N3~2S ~ HCI:
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-dihydro-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]-acetamide 3s (~}, the title compound is obtained as a white solid (77.6 %), mp 163-164 °C; MS
(+)FAB mle 318/320 (M+H+).
Elemental analysis for C16H16C1N302:
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, mp s >250 °C: MS EI mle 317/319 (M+).
Elemental analysis for C16H16C1N302 ~ HCI:
Calc'd: C, 54.25; H, 4.84; N) 11.86 Found: C, 54.18; H, 4.76; N, 11.87 to Example 9 4-(2-Benzylamino-ethoxy)-6-chloro-1,3-dihydro-benzoimidazol-2-one is Following the general procedure used in example 1 and using N-(4-chloro-benzyl)-2,2,2-trifluoro-N-[2-(6-chloro-2-oxo-2,3-dihydro-1 H-benzoimidazol-4-yloxy)-ethyl]-acetamide {5h) afforded the title compound as a white solid (77.6 %), mp 192-193 °C; MS
EI mle 317/319 (M+).
Elemental analysis for C16H16C1N302:
Calc'd: C, 60.48; H, 5.08; N, 13.22 Found: C, 60.24; H, 5.01; N, 13.09 2s Treatment of the free base with ethereal HCI gave the hydrochloride salt as a white solid, mp >250 °C: MS EI mle 317/319 (M+).
Elemental analysis for C16H16C1N302 ~ 1HC1:
Calc'd: C, 54.25; H, 4.84; N, 11.86 so Found: C, 54.23; H, 4.85; N, 11.69 Example 10 6-Chloro-4-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy~-1,3-dihydro benzoimidazol-2-one s to Following the general procedure used in example 1 and using N-[2-(6-chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-yimethyl-acetamide ~) afforded the title compound as a white solid (89.0 %), mp 179-180 °C; MS EI mle 323/325 (M+).
Elemental analysis for C14H14C1N302S:
Calc'd: C, 51.93; H, 4.36; N, 12.98 Found: C, 51.80; H, 4.23; N, 12.96 i s Treatment of the title compound with ethereal HCI gave the hydrochloride as a white solid(90.0 %), mp >250 °C: 1VIS EI mle 323/325 (M+).
Elemental analysis for C14H14C1N302S ~ HCI:
Calc'd: C, 46.68; H, 4.20; N, 11.66 2o Found: C, 46.52; H, 4.00; N, 11.57 Example 11 6-Chloro-4-{2-[(thiophen-3-ylmethyl)-amino]-ethoxy}-1,3-dihydro-2s benzoimidazol-2-one Following the general procedure used in. example 1 and using N-[2-(6-chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylinethyl-acetamide (~), the title compound is obtained as a white solid (89.0 %), mp 182-30 183 °C; MS (+)FAB mle 324/326 (M+H+).
Elemental analysis for C14H14C1N302S:
Calc'd: C, 51.93; H, 4.36; N, 12.98 Found: C, 51.96; H, 4.30; N, 12.95 3s 'The title compound was treated with ethereal HC1 to obtain the hydrochloride salt as a white solid (90.0% ), mp, >250 °C: MS EI mle 323/325 (M+).
Elemental analysis~for C14H14C1N302S ~ 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-2y1)-ethoxy]-1,3-dihydro-to benzoimidazol-2-one Following the general procedure used in example 1 and using 2-[2-(3,4-dihydro-1 H-isoquinolin-2-yl)-ethoxy)-6-vitro-phenylamine (~ afforded the title compound as a white solid (63.0 %)) mp 173-174 °C; MS EI mle 309 (M+).
is Elemental analysis for C 18H 19N302:
Calc'd: C, 69.88; H, 6.19; N, 13.58 Found: C) 69.48; H, 6.01; N, 13.55 2o Treatment of the free base with ethereal HCl gave a quarter hydrate of the hydrochloride salt as a white solid (90.0% ), mp >250 °C: MS EI mle 323/325 (M+).
Elemental analysis for C18H19N3O2 ~ HCl ~ 0.25 H20:
Calc'd: C, 61.71; H, 5.90; N, 11.99 2s Found: C, 61.90; H, 5.88; N, 11.97 Example 13 4-[2-(3-Phenyl-propylamine)-ethoxy]-1,3-dihydro-benzoimidazol-2-one so Following the general procedures used in intermediates 4 and 5 and example 1, N-[2-(2-amino-3-vitro-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 C1gH21N3O2~O.S HZO:
ss Calc'd: C, 67.48; H, 6.92; N, 13.12 Found: C, 67.81; H, 6.76; N, 13.51 Treatment of the free base with ethereal HCl gave the hydrochloride salt as a white solid (90.9%), mp 243-245 °C; MS (+)FAB mle 312 (M+H+).
Elemental analysis for C18H2tN30z~HCI:
s 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 t o 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.
1 s 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 3H-quinpiroie (Quin.) and various concentrations of test compound, filtered and washed and counted in a Betaplate scintillation counter.
2o High affinity for the dopamine D-2 receptor was established by the standard experimental test procedure of Fields, et al., Brain Res., 1 ~6, 578 ( 1977) and Yamamura et al., eds., Neurotransmitter Receptor Binding, Raven Press, N.Y. (1978) wherein homogenized limbic brain tissue is incubated with -~H-spiroperidol (Spiper.) and various concentrations of test compound, filtered and washed and shaken with Hydrofluor 2s scintillation cocktail (National Diagnostics) and counted in a Packard 460 ~ scintillation counter.
The results of the tests with compounds representative of this invention are given in the immediately following table Example ICSO (nM) ICgO
# D2 Quin. (nM) 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 55 13 0.30 30.0 100.(1 Pharmaceutical Composition s 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 i o 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, 1 s 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 2o 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 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, e.g., glycols) and their s 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 1 o 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 ~ 5 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 rransdermal patch containing the active compound and a Garner that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic 2o 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 2s devices may be used to realease the active ingredient into the blood stream such as a semipernleable 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 3o 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 ss 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.
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 form can be packaged compositions, for example packed powders) vials) ampoules, prefilled syringes or sachets containing liquids.
s 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.
Claims (20)
1. A compound having the formula wherein:
R1 is hydrogen or C1-C6 alkyl;
R2 is selected from hydrogen, straight-chain and branched C1-C10 alkyl, cyclohexylmethyl or -(CH2) m Ar where Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from C1-C6 alkyl, halogen, C1-C6 alkoxide and trifluoromethyl;
or NR1R2 is 1, 2, 3, 4-tetrahydroquinolin-1-yl or 1, 2, 3, 4-tetrahydroisoquinolin-2-yl;
m is 1-5;
n is 1 or 2;
R3 is hydrogen or C1-C6 alkyl;
Y is halogen, C1-C6 alkyl, and C1-C6 alkoxy;
or a pharmaceutically acceptable salt thereof.
R1 is hydrogen or C1-C6 alkyl;
R2 is selected from hydrogen, straight-chain and branched C1-C10 alkyl, cyclohexylmethyl or -(CH2) m Ar where Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from C1-C6 alkyl, halogen, C1-C6 alkoxide and trifluoromethyl;
or NR1R2 is 1, 2, 3, 4-tetrahydroquinolin-1-yl or 1, 2, 3, 4-tetrahydroisoquinolin-2-yl;
m is 1-5;
n is 1 or 2;
R3 is hydrogen or C1-C6 alkyl;
Y is halogen, C1-C6 alkyl, and C1-C6 alkoxy;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 which is 4-(2-benzylamino-ethoxy)-1,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 which is 4-[2-(4-methyl-benzylamino)-ethoxy]-1,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1 which is 4(7)-(2-benzylamino-ethoxy)-1-(3)-methyl-1,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 1 which is 4-(3-benzylamino-propoxy)-1,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.
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.
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.
10. A compound according to claim 1 which is 4-(2-benzylamino-ethoxy)-6-chloro-l,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-1H-isoquinolin-2y1)-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 D2 agonist which comprises administration to a mammal in need thereof of a therapeutically effective amount of a compound according to the formula wherein:
R1 is hydrogen or C1-C6 alkyl;
R2 is selected from hydrogen, straight-chain and branched C1-C10 alkyl, cyclohexylmethyl or -(CH2)m Ar where Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from C1-C6 alkyl, halogen, C1-C6 alkoxide and trifluoromethyl;
or NR1R2 is 1, 2, 3, 4-tetrahydroquinolin-1-yl or 1, 2, 3, 4-tetrahydroisoquinolin2-yl;
m is 1-5;
n is 1 or 2;
R3 is hydrogen or C1-C6 alkyl;
Y is halogen, C1-C6 alkyl, and C1-C6 alkoxy;
or a pharmaceutically acceptable salt thereof.
R1 is hydrogen or C1-C6 alkyl;
R2 is selected from hydrogen, straight-chain and branched C1-C10 alkyl, cyclohexylmethyl or -(CH2)m Ar where Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from C1-C6 alkyl, halogen, C1-C6 alkoxide and trifluoromethyl;
or NR1R2 is 1, 2, 3, 4-tetrahydroquinolin-1-yl or 1, 2, 3, 4-tetrahydroisoquinolin2-yl;
m is 1-5;
n is 1 or 2;
R3 is hydrogen or C1-C6 alkyl;
Y is halogen, C1-C6 alkyl, and C1-C6 alkoxy;
or a pharmaceutically acceptable salt thereof.
16. The method of treatment according to claim 15 wherein the disease treated is schizophrenia.
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.
20. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to the formula wherein:
R1 is hydrogen or C1-C6 alkyl;
R2 is selected from hydrogen, straight-chain and branched C1-C10 alkyl, cyclohexylmethyl or -(CH2)m Ar where Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from C1-C6 alkyl, halogen, C1-C6 alkoxide and trifluoromethyl;
or NR1R2 is 1, 2, 3, 4-tetrahydroquinolin-1-yl or 1, 2, 3, 4-tetrahydroisoquinolin2-yl;
m is 1-5;
n is 1 or 2;
R3 is hydrogen or C1-C6 alkyl;
Y is halogen, C1-C6 alkyl, and C1-C6 alkoxy;
or a pharmaceutically acceptable salt thereof.
R1 is hydrogen or C1-C6 alkyl;
R2 is selected from hydrogen, straight-chain and branched C1-C10 alkyl, cyclohexylmethyl or -(CH2)m Ar where Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from C1-C6 alkyl, halogen, C1-C6 alkoxide and trifluoromethyl;
or NR1R2 is 1, 2, 3, 4-tetrahydroquinolin-1-yl or 1, 2, 3, 4-tetrahydroisoquinolin2-yl;
m is 1-5;
n is 1 or 2;
R3 is hydrogen or C1-C6 alkyl;
Y is halogen, C1-C6 alkyl, and C1-C6 alkoxy;
or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US80187097A | 1997-02-18 | 1997-02-18 | |
| US08/801,870 | 1997-02-18 | ||
| PCT/US1998/000623 WO1998035946A1 (en) | 1997-02-18 | 1998-01-13 | 4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-one derivatives, their preparation and their use as dopamine autoreceptor (d2) agonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2278747A1 true CA2278747A1 (en) | 1998-08-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002278747A Abandoned CA2278747A1 (en) | 1997-02-18 | 1998-01-13 | 4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-one derivatives, their preparation and their use as dopamine autoreceptor (d2) agonists |
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| EP (1) | EP0964853A1 (en) |
| JP (1) | JP2001511804A (en) |
| KR (1) | KR20000071160A (en) |
| CN (1) | CN1138761C (en) |
| AR (1) | AR011138A1 (en) |
| AU (1) | AU744443B2 (en) |
| BR (1) | BR9807703A (en) |
| CA (1) | CA2278747A1 (en) |
| HU (1) | HUP0001262A3 (en) |
| IL (1) | IL131156A0 (en) |
| NZ (1) | NZ337271A (en) |
| TW (1) | TW383303B (en) |
| WO (1) | WO1998035946A1 (en) |
| ZA (1) | ZA981310B (en) |
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| GB9210632D0 (en) * | 1992-05-19 | 1992-07-01 | Fisons Plc | Compounds |
| IE914003A1 (en) * | 1990-11-20 | 1992-05-20 | Astra Pharma Prod | Biologically Active Amines |
| PT707007E (en) * | 1994-10-14 | 2002-06-28 | Merck Patent Gmbh | AMINO DERIVATIVES (TIO) ETER AS ACTIVE AGENTS IN THE CNS |
| IL119483A (en) * | 1995-11-06 | 1999-06-20 | American Home Prod | 2-(Aminomethyl)-3,4,7,9- tetrahydro- 2H-pyrano-2[3,3-e]indol-8-ones their derivatives and pharmaceutical compositions containing them |
| ES2179362T3 (en) * | 1996-08-27 | 2003-01-16 | Wyeth Corp | DERIVATIVES OF 4-AMINOETOXI INDOLONA. |
| EP0923576B1 (en) * | 1996-08-27 | 2002-11-06 | Wyeth | 4-aminoethoxy-indolone derivatives as dopamine d2 agonists |
-
1998
- 1998-01-13 NZ NZ337271A patent/NZ337271A/en unknown
- 1998-01-13 KR KR1019997007450A patent/KR20000071160A/en not_active Application Discontinuation
- 1998-01-13 AU AU60234/98A patent/AU744443B2/en not_active Ceased
- 1998-01-13 JP JP53572998A patent/JP2001511804A/en active Pending
- 1998-01-13 BR BR9807703-1A patent/BR9807703A/en not_active IP Right Cessation
- 1998-01-13 HU HU0001262A patent/HUP0001262A3/en unknown
- 1998-01-13 IL IL13115698A patent/IL131156A0/en unknown
- 1998-01-13 WO PCT/US1998/000623 patent/WO1998035946A1/en not_active Application Discontinuation
- 1998-01-13 EP EP98903469A patent/EP0964853A1/en not_active Withdrawn
- 1998-01-13 CA CA002278747A patent/CA2278747A1/en not_active Abandoned
- 1998-01-13 CN CNB988041197A patent/CN1138761C/en not_active Expired - Fee Related
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| Publication number | Publication date |
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| AR011138A1 (en) | 2000-08-02 |
| WO1998035946A1 (en) | 1998-08-20 |
| IL131156A0 (en) | 2001-01-28 |
| CN1138761C (en) | 2004-02-18 |
| AU6023498A (en) | 1998-09-08 |
| BR9807703A (en) | 2000-05-02 |
| EP0964853A1 (en) | 1999-12-22 |
| TW383303B (en) | 2000-03-01 |
| JP2001511804A (en) | 2001-08-14 |
| HUP0001262A2 (en) | 2001-04-28 |
| ZA981310B (en) | 1999-08-17 |
| CN1252060A (en) | 2000-05-03 |
| HUP0001262A3 (en) | 2002-04-29 |
| KR20000071160A (en) | 2000-11-25 |
| NZ337271A (en) | 2001-01-26 |
| AU744443B2 (en) | 2002-02-21 |
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