EP0964853A1 - 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

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Publication number
EP0964853A1
EP0964853A1 EP98903469A EP98903469A EP0964853A1 EP 0964853 A1 EP0964853 A1 EP 0964853A1 EP 98903469 A EP98903469 A EP 98903469A EP 98903469 A EP98903469 A EP 98903469A EP 0964853 A1 EP0964853 A1 EP 0964853A1
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Prior art keywords
dihydro
alkyl
benzoimidazol
pharmaceutically acceptable
ethoxy
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EP98903469A
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German (de)
French (fr)
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Richard Eric Mewshaw
James Albert Nelson
Uresh Shantilal Shah
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American Home Products Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • 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
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to a series of 4-aminoalkoxy-l,3-dihydrobenzoimidazol-2- ones having dopaminergic properties and thus have utility in treating Parkinson's disease, Tourette's syndrome, schizophrenia, and alcohol and drug addiction.
  • 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).
  • 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 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 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.
  • Ciba-Geigy discloses compounds represented by the compound of the formula below which have both ⁇ and ⁇ -adrenergic properties and are useful as cardiovascular and antihypertensive agents.
  • R 1 is hydrogen or C ⁇ -C 6 alkyl
  • R 2 is selected from hydrogen, straight-chain and branched Ci-Cio alkyl, cyclohexylmethyl or -(CH 2 ) m Ar where Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from - alkyl, halogen, C,-C 6 alkoxide and trifluoromethyl; or NR ! R 2 is 1, 2, 3, 4-tetrahydroquinolin-l-yl or 1, 2, 3, 4-tetrahydroisoquinolin- 2-yl; m is 1-5; n is 1 or 2;
  • R 3 is hydrogen or C,-C 6 alkyl
  • Y is halogen, - alkyl, and - alkoxy
  • the pharmaceutically acceptable salts thereof can be formed with an invention compound and a pharmaceutically acceptable acid including, but not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, acetate, fumarate, succinate, citrate, maleate, lactate, and benzoate salts.
  • the compounds of this invention are dopamine autoreceptor agonists, that is, they serve to modulate the synthesis and release of the 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 D 2 receptor and are thereby useful in the treatment of alcohol and drug addiction.
  • the compounds of Formula I are generally prepared by the overall sequence depicted in Schemes I -IV.
  • R 1 and R 2 is hydrogen
  • Scheme I outlines a procedure to prepare an invention compound where R 3 is H.
  • Scheme II shows a synthetic route for invention compounds where R 3 is not H.
  • Scheme III shows a synthetic route for invention compounds where neither of R 1 and R 2 is H.
  • Scheme IV shows the procedure used to prepare an intermediate where Y is Cl.
  • the fumarate salt was prepared by adding a solution of the free base (165 mg) in warm isopropanol (15 mL) to an excess of fumaric acid in warm isopropanol (20 mL). Upon completion of addition crystals began forming and the mixture was allowed to cool to room temperature and the crystals filtered to afford 203 mg of fumarate salt, mp 201.5-202.5 °C; MS ESI m/e 298 (M+H + ).
  • Intrinsic activity is predicted using die ratio of the "low-affinity agonist" (LowAg) state of the receptor and the "high-affinity agonist” (HighAg) state of the receptor, i.e. LowAg/HighAg. These ratios correlate with the agonist, partial agonist, and antagonist activities of a given compound, which activities characterize a compounds ability to elicit an antipsychotic effect.
  • Affinity for the dopamine autoreceptor was established by a modification of the standard experimental test procedure of Seemen and Schaus, European Journal of Pharmacology 203: 105-109, 1991, wherein homogenized rat striatal brain tissue is incubated with 3 H-quinpirole (Quin.) and various concentrations of test compound, filtered and washed and counted in a Betaplate scintillation counter.
  • High affinity for the dopamine D-2 receptor was established by the standard experimental test procedure of Fields, et al., Brain Res., 136. 578 (1977) and Yamamura et al., eds., Neurotransmitter Receptor Binding, Raven Press, N.Y.
  • compositions 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.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties n suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
  • the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
  • a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
  • the liquid carrier can contain other suitable pharmaceutical additives such a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • 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 derivatives, and oils (e.g., fractionated coconut oil and arachis oil).
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be as either a liquid or a solid dosage form.
  • the compounds of this invention may be administered rectally in the form of a conventinal suppository.
  • the compounds of this invention may be formulated into an aqueous or partrially aqueous solution, which can then be utilized in die form of an aerosol.
  • the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
  • the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments may be viscous liquid or semi-solid emulsions of either the oil in water or water in oil type.
  • Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
  • a variety of occlusive devices may be used to realease the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in d e literature.
  • the dosage to be used in the treatment of a specific patient suffering a dopamine imbalance must be subjectively determined by the attending physician.
  • the variables involved include the severity of the dysfunction, and the size, age, and response pattern of the patient.
  • the pharmaceutical composition is in unit dosage form, e.g., as tablets or capsules.
  • the composition is sub-divided in unit dose containing appropriate quantities of die active ingredient;
  • the unit dosage form can be packaged compositions, for example packed powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

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Abstract

Disclosed are compounds of formula (I), wherein R1 is hydrogen or C¿1?-C6 alkyl; R?2¿ is selected from hydrogen, straight-chain and branched C¿1?-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 NR?1R2¿ 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 C¿1?-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-DIHYDROBENZOIMIDAZO -2-ONE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS DOPAMINE AUTORECEPTOR (D2) AGONISTS
Field of Invention
This invention relates to a series of 4-aminoalkoxy-l,3-dihydrobenzoimidazol-2- ones having dopaminergic properties and thus have utility in treating Parkinson's disease, Tourette's syndrome, schizophrenia, and alcohol and drug addiction.
Background of the Invention
The compounds of this invention are dopamine agonists having various degrees of intrinsic activity and are essentially free from extrapyramidal side effects. Some of the compounds are selective autoreceptor agonists, and therefore partial agonists (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). 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 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 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 α and β-adrenergic properties and are useful as cardiovascular and antihypertensive agents.
CGP- 12177
Summary of the Invention
Compounds of this invention are 4-aminoalkoxy-l,3-dihydro-benzoimidazol-2- ones which are illustrated by Formula I below
I wherein:
R1 is hydrogen or Cι-C6 alkyl;
R2is selected from hydrogen, straight-chain and branched Ci-Cio 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 - alkyl, halogen, C,-C6 alkoxide and trifluoromethyl; or NR!R2 is 1, 2, 3, 4-tetrahydroquinolin-l-yl or 1, 2, 3, 4-tetrahydroisoquinolin- 2-yl; m is 1-5; n is 1 or 2;
R3 is hydrogen or C,-C6 alkyl; Y is halogen, - alkyl, and - alkoxy; and the pharmaceutically acceptable salts thereof. Acid addition salts can be formed with an invention compound and a pharmaceutically acceptable acid including, but not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, acetate, fumarate, succinate, citrate, maleate, lactate, and benzoate salts.
The compounds of this invention are dopamine autoreceptor agonists, that is, they serve to modulate the synthesis and release of the 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 D2 receptor and are thereby useful in the treatment of alcohol and drug addiction.
Detailed Description of the Invention
The compounds of Formula I are generally prepared by the overall sequence depicted in Schemes I -IV. When one or both of R1 and R2 is hydrogen, it is desirable to protect the basic nitrogen with a suitable protecting group such as the trifluoroacetyl group or t-butyloxycarbonyl group. Scheme I outlines a procedure to prepare an invention compound where R3 is H.
Scheme I
Scheme II shows a synthetic route for invention compounds where R3 is not H.
Scheme II
BoczO
Boc
Scheme III shows a synthetic route for invention compounds where neither of R1 and R2 is H. Scheme III
Scheme IV shows the procedure used to prepare an intermediate where Y is Cl.
Scheme IV
The following specific examples illustrate the synthetic procedures for the preparation of intermediates and invention compounds and should not be construed as limiting the scope of this disclosure. Those skilled in the art of organic synthesis may be aware of still other routes to prepare invention compounds. Reactants and intermediates are either commercially available or can be prepared according to standard literature procedures. Intermediate la
2-(2-Chloro-ethoxy)-6-nitro-phenylamine
Method 1.
To a solution of 2-amino-3-nitrophenol (5.0 g, 32.4 mmol), triphenylphosphine (12.8 g, 48.7 mmol) and 2-chloroethanol (3.9 g, 48.7 mmol) in tetrahydrofuran (120 mL) at 0 - 5° C was added over 30 min a solution of diethyl azodicarboxylate (8.5 g, 48.7 mmol) in tetrahydrofuran (75 mL). The mixture was warmed to 23° C and stirred for 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 m/e 216/218 (M+).
Elemental analysis for C8H9CIN2O3:
Calc'd: C, 44.36; H, 4.19; N, 12.93 Found: C, 44.45; H, 4.02; N, 12.97
Method 2.
A slurry containing 2-amino-3-nitrophenol (32.0 g, 0.208 mol), 1,2-dichloroethane (260.0 g, 2.65 mol), potassium carbonate (35.0 g, 0.252 mol) and 2-butanone (750 mL) was refluxed for 24 hr. The mixture was cooled, filtered and the solids were washed with ethyl acetate. The filtrate was concentrated to an oily residue that was dissolved in ethyl acetate (500 mL). The organic layer was washed with 1 N sodium hydroxide (250 mL), water (500 mL), and brine (2X 500 mL), dried over anhydrous magnesium sulfate. Concentration of the filtered solution and trituration of the residue with hexane afforded 37.8 g (84.6%) of product as an orange solid, mp 71-73 °C; MS (+)PBEI m/e 216/218 (M+).
Intermediate lb 2-(3-Bromo-propoxy)-6-nitro-phenylamine
Following the procedure of method 2 above, and using 1,3-dibromopropane, the title compound was as a yellow solid, (78.7%) mp 88-89 °C; MS El m/e 214/216 (M+).
Elemental analysis for C9H1 ιBrN2θ3: 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-BenzyIamino-ethoxy)-6-nitro-phenylamine
A mixture of 2-(2-chloro-ethoxy)-6-nitiO-phenylamine (la, 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 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 El m/e 287 (M+).
Elemental analysis for C15H17N3O3:
Calc'd: C, 62.71; H, 5.96; N, 14.62 Found: C, 62.64; H, 6.04; N, 14.23 DMSO can be used as a solvent in this reaction
Using this general procedure and utilizing 2-(2-chloro-ethoxy)-6-nitτo-phenylamine or 2-(3-bromo-propoxy)-6-nitro-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-benzylamine, thiophene-3-methyl- amine, 1,2,3,4-tetrahydroisoquinoline or 3-phenyl-l-propylamine produced the following intermediates 2b-21, respectively:
2b 2-[2-(4-Methyl-benzyIamino)-ethoxy]-6-nitro-phenylamine as a yellow solid (89 %), mp 55-57 °C; El m/e 301 (M+).
Elemental analysis for C16H19N3O3:
Calc'd: C, 62.71; H, 5.96; N, 14.62 Found: C, 62.64; H, 6.04; N, 14.23
2c 2-(3-Benzylamino-propoxy)-6-nitro-phenylamine as a viscous orange oil (85.5 %); MS El m/e 301 (M+).
Elemental analysis for C16H19N3O3: Calc'd: C, 63.77; H, 6.36; N, 13.94 Found: C, 63.66; H, 6.28; N, 13.89
2d 2-{2-[(Naphthalen-l-ylmethyl)-amino]-ethoxy}-6-nitro-phenylamine as a yellow solid (76.3 %), mp 66-67 °C; MS El m/e 337 (M+).
Elemental analysis for C19H19N3O3: Calc'd: C, 67.64; H, 5.68; N, 12.45 Found: C, 67.20; H, 5.66; N, 12.26
2e 2-[2-(4-tert-ButyIbenzylamino)-ethoxy]-6-nitro-phenyIamine as an orange viscous oil (83.3 %); MS El m/e 343 (M+).
Elemental analysis for C19H25N3O3 ♦ 0.25 H2O: Calc'd: C, 65.59; H, 7.39; N, 12.07 Found: C, 65.89; H, 7.20; N, 11.94
2f 2-Nitro-6-{2-[(thiophen-2-yImethyI)-amino]-ethoxy}-phenylamine as a red semi-solid material (88.5%); MS El m/e 389 (M+).
Elemental analysis for C13H15N3O3S:
Calc'd: C, 53.23; H, 5.15; N, 14.32 Found: C, 52.86; H, 4.93; N, 14.15
2g 2-[2-(4-Chloro-benzylamino)-ethoxy]-6-nitro-phenylamine as an orange solid (87.8 %), mp 61-62 °C; MS El m/e 322/324 (M+).
Elemental analysis for C15H16N3O3 • 0.25 H2O: Calc'd: C, 55.22; H, 5.10; N, 12.88 Found: C, 55.27; H, 4.96; N, 12.88
2h 2-(2-Benzylamino-ethoxy)-4-chloro-6-nitro-phenylamine as a orange- brown colored solid (54.0 %), mp 87-88 °C; MS El m/e 321/323 (M+).
Elemental analysis for C15H16CIN3O3: Calc'd: C, 55.99; H, 5.01; N, 13.06
Found: C, 55.85; H, 4.90; N, 13.13 2i 4-ChIoro-2-nitro-6-{2-[(thiophen-2-ylmethyI)-amino]-ethoxy}- phenylamine as a yellow solid (44.0 %), mp 74-75 °C; MS El m/e 327/329 (M+).
Elemental analysis for C13H14CIN3O2S: Calc'd: C, 47.67; H, 4.33; N, 12.75 Found: C, 47.54; H, 4.11; N, 13.06
2j 4-ChIoro-2-nitro-6-{2-[(thiophen-3-yImethyl)-amino]-ethoxy}- phenylamine as a yellow solid (33.3 %), mp 77-78 °C; MS El m/e 327/329 (M+).
Elemental analysis for C13H14CIN3O2S: Calc'd: C, 47.67; H, 4.33; N, 12.75 Found: C, 47.54; H, 4.18; N, 12.80
2k 2-[2-(3,4-Dihydro-lH-isoquinolin-2-yl)-ethoxy]-6-nitro-phenyIamine as a yellow solid (87.1 %), mp 95-97 °C; MS El m/e 313 (M+).
Elemental analysis for C17H19N3O2: Calc'd: C, 65.16; H, 6.11; N, 13.41 Found: C, 64.87; H, 6.11; N, 13.40
21 2-Nitro-6--[2-(-phenyl-propylamino)-ethoxy]-phenylarnine as a viscous orange oil (83.9%); MS El m/e 315 (M+).
Elemental analysis for C17H21N3O3 »0.25 H2O:
Calc'd: C, 63.83; H, 6.77; N, 13.14 Found: C, 63.90; H, 6.56; N, 13.07
Intermediate 3a
N-[2-(2-Amino-3-nitro-phenoxy)-ethyl]-N-benzyI-2,2,2-trifluoro-acetamide
To a solution of 2-(2-benzylamino-ethoxy)-6-nitro-phenylamine (2a, 0.5 g, 1.74 mmol) and triethylamine (0.32 mL, 3.48 mmol) in anhydrous methylene chloride (10 mL) 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 El m/e 383 (M+).
Elemental analysis for Cl7Hi6F?3N3θ4: 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-nitro-phenylamine, 2-(3-benzylamino-propoxy)-6-nitro-phenylamine, 2- { 2-[(naphthalen- l-ylmethyl)-amino]-ethoxy}-6-nitro-phenylamine, 2-[2-(4-tert-butylbenzylamino)-ethoxy]- 6-nitiO-phenyl-amine, 2-nitiO-6-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy}-phenylamine, 2-[2-(4-chloro-benzylamino)-ethoxy]-6-nitro-phenylamine, 2-(2-benzylamino-ethoxy)-4- chloro-6-nitro-phenylamine, 4-chloro-2-nitro-6-{2-[(thiophen-2-ylmethyl)-amino]- ethoxy } -phenylamine, 4-chloro-2-nitro-6- { 2-[(thiophen-3-ylmethyl)-amino]-ethoxy } - phenylamine and 2-nitro-6-[2-(3-phenyl-propylamino)-ethoxy]-phenylamine gave respectively:
3b N-[2-(2-Amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-(4-methyl- benzyl) acetamide as a yellow solid (79 %), mp 172-173 °C; MS El m/e 397 (M+).
Elemental analysis for C18H18F3N3O4: Calc'd: C, 54.41; H, 4.57; N, 10.58 Found: C, 54.34; H, 4.33; N, 10.53
3c N-[3-(2-Amino-3-nitro-phenoxy)-propyI]-N-benzyl-2,2,2-trifIuoro- acetamide as a yellow solid (67.8 %), mp 92-93 °C; MS El m/e 397 (M+).
Elemental analysis for Cl8Hi8F3N3θ4: Calc'd: C, 54.41; H, 4.57; N, 10.58 Found: C, 54.30; H, 4.50; N, 10.50
3d N-[2-(2-Amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N- naphthalen-l-ylmethyl-acetamide as a yellow-orange colored solid (75.3 %), mp 133-135 °C; MS El m/e 433 (M+).
Elemental analysis for C21H1 F3N3O4; Calc'd: C, 58.20; H, 4.19; N, 9.70 Found: C, 58.28; H, 4.07; N, 9.48
3e N-[2-(2-Amino-3-nitro-phenoxy)-ethyI]-N-(4-tert-butyl-benzyl)-
2,2,2-trifluoro-acetamide as a yellow solid (82.0 %), mp 80-82 °C; MS El m/e 439 (M+).
Elemental analysis for C21H24F3N3O4:
Calc'd: C, 57.40; H, 5.51; N, 9.56 Found: C, 57.09; H, 5.31; N, 9.40
3f N-[2-(2-Amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-
2-ylmethyl-acetamide as a yellow solid (77.4 %), mp 143-144 °C; MS El m/e 389 (M+).
Elemental analysis for C15H14F3N3O4S: Calc'd: C, 46.27; H, 3.62; N, 10.79
Found: C, 46.19; H, 3.39; N, 10.64
3g N-[2-(2-Amino-3-nitro-phenoxy)-ethyI]-N-(4-chloro-benzyI)-2,2,2- trifluoro-acetamide as a yellow solid (84.0 %), mp 138-139 °C; MS (+)FAB m/e 418/420 (M+H+)
Elemental analysis for C17H15CIF3N3O4: Calc'd: C, 48.88; H, 3.62; N, 10.06 Found: C, 48.66; H, 3.47; N, 9.82
3h N-[2-(2-Amino-5-chloro-3-nitro-phenoxy)-ethyl]-N-benzyI-2,2,2- trifluoro-acetamide as a yellow solid (67.9 %), mp 106-108 °C; MS (+)FAB m/e 418/420 (M+H+).
Elemental analysis for C17H15CIF3N3O4:
Calc'd: C, 48.88; H, 3.62; N, 10.06 Found: C, 48.96; H, 3.50; N, 10.03
3i N-[2-(2-Amino-5-chIoro-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N- thiophen-2-ylmethyI-acetamide as a yellow solid (59.6 %), mp 97-98 "C; MS El m/e 423/425 (M+). Elemental analysis for C15H13CIF3N3O4S: Calc'd: C, 42.51; H, 3.09; N, 9.92 Found: C, 42.37; H, 2.97; N, 9.84
3j N-[2-(2-Amino-5-chIoro-3-nitro-phenoxy)-ethyI]-2,2,2-trifIuoro-N- thiophen-3-ylmethyl-acetamide as a yellow solid (80.0 %), mp 149-150 °C; MS El m/e 423/425 (M+).
Elemental analysis for C15H13CIF3N3O4S: Calc'd: C, 42.51; H, 3.09; N, 9.92
Found: C, 42.02; H, 2.95; N, 9.78
2k N-[2-(2-amino-3-nitro-phenoxy)-ethyI]-2,2,2-trifIuoro-N-(3-phenyl- propyl)-acetamide as a yellow solid (72.6%), mp 81-82 °C; MS El m/e 411 (M+).
Elemental analysis for C19H20F3N3O4: Calc'd: C, 55.47; H, 4.90; N, 10.21 Found: C, 55.57; H, 4.66; N, 10.23
Intermediate 4a
N-Benzvl-N-r2-f2.3-diamino-phenoxv)-ethvll-2.2.2-trifluoro-acetamide
To a mixture of N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro- acetamide a, 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 floe 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 (+)FAB m/e 354 (M+H+).
Elemental analysis for C17H18F3N3O2: Calc'd: C, 56.58; H, 4.72; N, 12.38 Found: C, 57.49; H, 5.10; N, 11.86
Following the above procedure and utilizing N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-2,2,2- trifluoro-N-(4-methyl-benzyl) acetamide, N-[3-(2-amino-3-nitro-phenoxy)-propyl]-N- benzyl-2,2,2-trifluoro-acetamide, N-[2-(2-amino-3-nitto-phenoxy)-ethyl]-2,2,2-trifluoro- N-naphthalen- 1 -yimethyl-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- 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- niuO-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide afforded respectively:
4b N-[2-(2,3-Diamino-phenoxy)-ethyI]-2,2,2-trifIuoro-N-(4-methyI- benzy -acetamide as a white solid (85.0 %), mp 94-96 °C; MS El m/e 367 (M+).
Elemental analysis for C18H20F3N3O2: 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-trifIuoro- acetamide as a white solid (86.5 %), mp 56-58 °C; MS El m/e 367 (M+).
Elemental analysis for C18H20F3N3O2:
Calc'd: C, 58.85; H, 5.49; N, 11.44 Found: C, 59.00; H, 5.42; N, 11.48
4d N-[2-(2,3-Diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-naphthalen-l- ylmethyl-acetamide as a viscous yellow oil (63.0 %); MS (+)FAB m/e 404 (M+H ).
Elemental analysis for C21H20F3N3O2: Calc'd: C, 62.53; H, 5.00; N, 10.42 Found: C, 62.45; H, 4.98; N, 10.20
4e N-(4-tert-Butyl-benzyl)-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2- trifluoro-acetamide as a viscous brown oil (72.7 %); MS El m/e 409 (M+).
4f N-[2-(2,3-Diamino-phenoxy)-ethyl]-2,2,2-trifIuoro-N-thiophen-2- ylmethyl-acetamide as a white solid (41.0 %), mp 72-74 °C; MS (+)FAB m/e 404 (M+H+). Elemental analysis for C15H16F3N3O2S:
Calc'd: C, 50.13; H, 4.49; N, 11.69
Found: C, 50.09; H, 4.38; N, 11.59
4g N-(4-ChIoro-benzyI)-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2- trifluoro-acetamide as a brown oil (80.9 %); MS El m/e 387/389 (M+).
Elemental analysis for C17H17CIF3N3O2: 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)-ethyI]-2,2,2- trifluoro-acetamide as a viscous brown oil (76.2 %); MS El m/e 387/389 (M+).
Elemental analysis for C17H17CIF3N3O2: Calc'd: C, 52.65; H, 4.42; N, 10.84 Found: C, 52.47; H, 4.39; N, 10.90
4i N-[2-(2,3-Diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-N- thiophen-2-yImethyI-acetamide as a viscous brown oil (71.4 %); MS El m/e 393/395 (M+).
Elemental analysis for C15H15CIF3N3O2S: Calc'd: C, 45.75; H, 3.84; N, 10.67
Found: C, 45.58; H, 3.93; N, 10.64
4j N-[2-(2,3-Diamino-5-chloro-phenoxy)-ethyI]-2,2,2-trifIuoro-N- thiophen-3-yImethyl-acetamide as a viscous brown oil (75.0 %); MS El m/e 393/395 (M+).
Elemental analysis for C15H15CIF3N3O2S: 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-lH-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 mmol) 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. 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 El m/e 379 (M+).
Elemental analysis for C18H16F3N3O3: Calc'd: C, 56.99; H, 4.25; N, 11.08
Found: C, 57.09; H, 4.07; 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-trifluoro-acetamide, N- [2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-naphthalen- 1 -yimethyl-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- 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:
5b 2,2,2-Trifluoro-N-(4-methyI-benzyl)-N-[2-(2-oxo-2,3-dihydro-lH- benzoimidazol-4-yloxy)-ethyI]-acetamide • 0.1 ethyl acetate as a white solid (96.6 %), mp 194-196 °C; MS (+)FAB m/e 394 (M+H+).
Elemental analysis for C19H18F3N3O3 ♦ 0.1 C4H8O2 Calc'd: C, 57.94; H, 4.71; N, 10.45 Found: C, 57.90; H, 4.60; N, 10.19 5c N-Benzyl-2,2,2-trifluoro-N-[3-(2-oxo-2,3-dihydro-lH- benzoimidazoI-4-yloxy)-propyl]-acetamide as a white solid (86.0 %), mp 114-116 °C; MS (+)FAB m/e 394 (M+H+).
Elemental analysis for C19H18F3N3O3
Calc'd: C, 58.01; H, 4.61; N, 10.68 Found: C, 57.67; H, 4.37; N, 10.49
5d 2,2,2-Trifluoro-N-naphthalen-l-ylmethyl-N-[2-(2-oxo-2,3-dihydro- lH-benzoimidazol-4-yloxy)-ethyI]-acetamide as a white solid (90.0 %), mp 88-90 °C; MS El m/e 429 (M+).
Elemental analysis for C22H18F3N3O3 Calc'd: C, 61.54; H, 4.23; N, 9.79 Found: C, 61.34; H, 4.25; N, 9.52
5e N-(4-tert-ButyI-benzyl)-2,2,2-trifIuoro-N-[2-(2-oxo-2,3-dihydro- lH-benzoimidazol-4-yloxy)-ethyl]-acetamide as a white solid (84.9 %), mp 184- 185 °C; MS El m/e 435 (M+).
Elemental analysis for C22H24F3N3O3
Calc'd: C, 60.68; H, 5.55; N, 9.65 Found: C, 60.59; H, 5.55; N, 9.66
5f 2,2,2-Trifluoro-N-[2-(2-oxo-2,3-dihydro-lH-benzoimidazol-4- yloxy)-ethyl]-N-thiophen-2-ylmethyl-acetamide as a white solid (73.3 %), mp 49-50 °C; MS El m/e 385 (M+).
5g N-(4-Chloro-benzyl)-2,2,2-trifIuoro-N-[2-(2-oxo-2,3-dihydro-lH- benzoimidazol-4-yIoxy)-ethyl]-acetamide as a white solid (56.7 %), mp 190-192 °C; MS (+)FAB m/e 414/416 (M+H+).
Elemental analysis for C18H15CIF3N3O3 Calc'd: C, 52.25; H, 3.65; N, 10.16 Found: C, 52.28; H, 3.55; N, 10.20 5h N-Benzyl-N-[2-(6-chloro-2-oxo-2,3-dihydro-lH-benzoimidazol-4- yloxy)-ethyl]-2,2,2-trifIuoro-acetamide as a white solid (60.0 %), mp 171-173 °C; MS (+)APCI m/e 414.2/416.2 (M+H+).
Elemental analysis for C 18H 15CIF3N3O3
Calc'd: C, 52.25; H, 3.65; N, 10.16 Found: C, 52.10; H, 3.56; N, 9.96
5i N-[2-(6-Chloro-2-oxo-2,3-dihydro-lH-benzoimidazoI-4-yIoxy)- ethyl]- 2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide as a white solid (70.1 %), mp 153-154 °C; MS El m/e 419/421 (M+).
Elemental analysis for C16H13CIF3N3O3S: Calc'd: C, 45.78; H, 3.12; N, 10.01 Found: C, 45.85; H, 3.02; N, 9.73
5j N-[2-(6-Chloro-2-oxo-2,3-dihydro-lH-benzoimidazol-4-yIoxy)- ethyl]- 2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide as a white solid (77.8 %), mp 152-153 °C; MS El m/e 419/421 (M+).
Elemental analysis for C16H13CIF3N3O3S: 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-trifIuoro-acetamide
To a suspension of N-[2-(2-amino-3-nitto-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) 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 m/e 480 (M+H+). Elemental analysis for C19H15F6N3O5 Calc'd: C, 47.61; H, 3.15; N, 8.77 Found: C, 47.35; H, 2.94; N, 8.69
Intermediate 7
N-[2-(l-MethyI-2-{2,2,2-Trifluoroacetamidyl}-3-nitro-phenoxy)-ethyl]-N- benzyl-2,2,2-trifluoro-acetamide
A suspension of potassium carbonate (1.44g, 10.4 mmol), N-[2-(2-{ 2,2,2- trifluoroacetarnidyl}-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide (1.0 g, 2.09 mmol) and methyl iodide (2.96 g, 20.9 mmol, previously filtered through basic alumina) in anhydrous dimethylsulfoxide (11 mL) was allowed to stir at room temperature for 24 h. The reaction mixture was poured into methylene chloride (200 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 yellow solid, mp 90-92.5 °C; MS m/e El 493 (M+).
Elemental analysis for C20H17F6N3O5 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-l-methyl-(2- { 2,2,2- trifluoroacetamidyl } -3-nitio-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 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-2- (methylamino-3-nitiO-phenoxy)ethylamine as a red oil; MS FAB m/e 302 (M+H+).
Intermediate 9
N-Benzyl-[2-(2-methylamino-3-nitro-phenoxy)-ethyl]-carbamic acid tert- butyl ester
A solution of N-benzyl-2-(2-methylamino-3-nitiO-phenoxy)-ethylamine (480 mg, 1.59 mmol) and di-tert-butyl dicarbonate (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 m/e El 401 (M+).
Elemental analysis for C21H27N3O5 Calc'd: C, 62.83; H, 6.78; N, 10.47 Found: C, 62.78; H, 6.53; N, 10.51
Intermediate 10
N-Benzyl-[2-(2-methylamino-3-amino-phenoxy)-ethyl]-carbamic acid tert- butyl ester
To a mixture of N-benzyl-[2-(2-methylamino-3-nitro-phenoxy)-ethyl]-carbamic acid tert-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 the solvent removed. Purification by chromatography (30 % ethyl acetate-hexane) afforded 380 mg (78.9 %) of a clear oil; MS El m/e 371 (M+); IR (film) 3400, 3350, 1680 cm-1. Intermediate 11
N-Benzyl-[2-(2-oxo-l,3-dihydro-benzoimidazol-4-yloxy)-ethyI]-carbamic acid tert-butyl ester
A mixture of N-benzyl-[2-(2-methylamino-3-amino-phenoxy)-ethyl]-carbamic acid tert-butyl ester (330 mg, 0.89 mmol) and diimidazole carbonyl (577 mg, 3.56 mmol) in anhydrous tetrahydrofuran (30 mL) was stirred a room temperature for 0.5 h and then heated to reflux for 3 h. The reaction was poured into water and extracted with ethyl acetate (2 x 150 mL). The organic layer dried over anhydrous magnesium sulfate, filtered, and the solvent removed. Purification by chromatography (50 % ethyl acetate-hexane) afforded 268 mg (75.8 %) of a foam; MS FAB m/e 398 (M+H+); IR (KBr) 3420, 3250, 1690 (bs) cm-1.
Intermediate 12
3-[2-(3,4-Dihydro-lH-isoquinolin-2-yl)-ethoxy]-benzene-l,2-diamine
The general procedure used in intermediate 4 using 2-[2-(3,4-dihydro-lH- isoquinolin-2-yl)-ethoxy]-6-nitro-phenylamine (2k) afforded 3-[2-(3,4-dihydro-lH- isoquinolin-2-yl)-ethoxy]-benzene-l,2-diamine as a solid (95 %), mp 76-77 °C. This material was characterized as the dihydrochloride 0.4 H2O salt; MS El m/e 283 (M+).
Elemental analysis for C17H21N3O • 2 HC1 • 0.4 H2O: Calc'd: C, 56.17; H, 6.60; N, 11.56 Found: C, 56.15; H, 6.68; N, 11.25
Intermediate 13
4-Chloro-2-(2-chloro-ethoxy)-6-nitro- phenylamine
A solution of 2-(2-chloro-ethoxy)-6-nitro-phenylamine Qa, 30.0 g, 0.14 mol), N- chlorosuccinamide and acetonitiile (1.3 L) was refluxed for 4 hr. The mixture was concentrated under vacuum and the residue was diluted with ethyl acetate (500 mL). The organic layer was washed with water (2X, 250 mL) and brine (250 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give an orange solid residue. Crystallization from ethyl acetate-hexane gave 33.5g (95.3 %) as orange solid, mp 109-110 °C; MS El m/e 250/252/254 (M+).
Elemental analysis for C8H8CI2N2O3: Calc'd: C, 38.27; H, 3.21; N, 11.16 Found: C, 38.15; H, 3.10; N, 10.96
Example 1
4-(2-Benzylamino-ethoxy)-l,3-dihydro-benzoimidazol-2-one
A suspension of potassium carbonate (1.15 g, 8.34 mmol) and N-benzyl-2,2,2- trifluoro-N-[2-(2-oxo-l ,3-dihydro-lH-benzoimidazol-4-yloxy)-ethyl]-acetamide (0.38g, 1.00 mmol) in methanol- water (30 mL:2 mL) was heated to reflux for 2 hr then the solvent was evaporated and the residue dissolved in ethyl acetate (100 mL) and extracted with water (80 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give the title compound as a white solid, mp 132-135°C. Without further purification, this material was dissolved in ethyl acetate- methanol (1:1) and treated with an excess amount of 1 N HC1 in ether to afford 0.30g (75.0%) of the hydrochloride salt as a light tan-colored solid, mp 230-233 °C: MS El m/e 283 (M+).
Elemental analysis for C 16H 17N3O2ΗCI
Calc'd: C, 60.09; H, 5.67; N, 13.14 Found: C, 59.84; H, 5.59; N, 12.92
Example 2
4-[2-(4-Methyl-benzylamino)-ethoxy]-l,3-di hydro- benzoimidazol-2-one
Following the general procedure used in example 1 and utilizing 2,2,2-trifluoro-N- (4-methyl-benzyl)-N-[2-(2-oxo-2,3-dihydro-lH-benzoimidazol-4-yloxy)-ethyl]-acetamide • 0.1 ethyl acetate (5b) afforded the title compound as a white solid (64.5 %), mp 162-163 °Q MS (+)FAB m/e 298 (M+H+). Treatment of the free base with ethereal HC1 gave a white solid (90.0 %), mp 244-246 °C: MS (+)FAB m/e 298 (M+H+).
Elemental analysis for CπHi9N3θ2*1.0 HC .7 H2O Calc'd: C, 56.17; H, 6.46; N, 11.56 Found: C, 55.94; H, 6.05; N, 11.42.
Example 3
4(7)-(2-Benzylamino-ethoxy)-l-(3)-methyl-l,3-dihydro-benzoimidazoI-2- one
To a solution of N-benzyl-[2-(2-oxo-l,3-dihydro-benzoimidazol-4-yloxy)-ethyl]- 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 170 mg (87 %) a white solid: mp 137-138°C; MS FAB 298 (M+H+). The fumarate salt was prepared by adding a solution of the free base (165 mg) in warm isopropanol (15 mL) to an excess of fumaric acid in warm isopropanol (20 mL). Upon completion of addition crystals began forming and the mixture was allowed to cool to room temperature and the crystals filtered to afford 203 mg of fumarate salt, mp 201.5-202.5 °C; MS ESI m/e 298 (M+H+).
Elemental analysis for Ci7Hi9N3θ2»C4H4θ4
Calc'd: C, 61.01; H, 5.61; N, 10.16 Found: C, 60.73; H, 5.36; N, 9.95
Example 4
4-(3-Benzylamino-propoxy)-l,3-dihydro-benzoimidazol-2-one
Following the general procedure used in example 1 and using N-benzyl-2,2,2- trifluoro-N-[3-(2-oxo-2,3-dihydro- lH-benzoimidazol-4-yloxy)-propyl]-aceιamide (5c) afforded the title compound as a light yellow solid foam (90.4 %); MS El m/e 297 (M+). Treatment of the free base with ethereal HC1 gave the hydrochloride salt as a white solid (63.9 %), mp 243-244 °C: MS El m/e 297 (M+). Elemental analysis for C17H19N3O2 • HCl: Calc'd: C, 61.17; H, 6.04; N, 12.59 Found: C, 60.92; H, 5.95; N, 12.41
Example 5
4-{2-[(NaphthaIen-l-ylmethyl)-amino]-ethoxy}-l,3-dihydro- benzoimidazol-2-one
Following the general procedure used in example 1 and using 2,2,2-trifluoro-N- naphthalen-l-ylmethyl-N-[2-(2-oxo-2,3-dihydro-lH-benzoimidazol-4-yloxy)-ethyl]- acetamide (5d) gave the title compound as a white solid (67.4 %); MS El m/e 333 (M+).
Elemental analysis for C20H19N3O2:
Calc'd: C, 72.05; H, 5.74; N, 12.60 Found: C, 71.72; H, 5.76; N, 12.22
Treatment of the free base with ethereal HCl gave the quarter hydrate of the HCl as a white solid (63.9 %), mp 223-225 °C: MS El m/e 333 (M+).
Elemental analysis for C17H19N3O2 • 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-tert-Butyl-benzylamino)-ethoxy]-l,3-dihydro-benzoimidazol-2-one
Following the general procedure used in example 1 and using N-(4-tert-buιyl- benzyl)-2,2,2-trifluoro-N-[2-(2-oxo-2,3-m^yα o-lH-benzoimidazol-4-yloxy)-ethyl]- acetamide (5e) gave the title as a white solid (84.5 %); MS El m/e 339 (M+).
Elemental analysis for C20H25N3O2:
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 HCl gave the hemihydrated HCl salt as a white solid, mp 224-226 °C: MS El m/e 339 (M+).
Elemental analysis for C20H25N3O2 • HCl • hemihydrate: Calc'd: C, 62.41; H, 7.07; N, 10.92
Found: C, 62.64; H, 6.93; N, 10.88
Example 7
4-{2-[(Thiophen-2-ylmethyI)-amino]-ethoxy}-l,3-dihydro-benzoimidazol-
2-one
Following the general procedure used in example 1 and using 2,2,2-trifluoro-N-[2- (2-oxo-2,3-dihydro-lH-benzoimidazol-4-yloxy)-ethyl]-N-thiophen- 2- yimethyl-acetamide (5f), the title compound is obtained as a white solid (76.8 %); MS El m/e 289 (M+).
Elemental analysis for C14H15N3O2S: Calc'd: C, 56.36; H, 5.41; N, 14.08 Found: C, 56.42; H, 5.04; N, 14.21
Conversion of the free base to the HCl salt with ethereal gave a white solid, mp 240-241 °C: MS El m/e 289 (M+).
Elemental analysis for C14H15N3O2S • HCl:
Calc'd: C, 51.61 ; H, 4.95; N, 12.90 Found: C, 51.22; H, 4.82; N, 12.70
Example 8
4-[2-(4-Chloro-benzylamino)-ethoxy]-l,3-dihydro-benzoimidazoI-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 (5g), the title compound is obtained as a white solid (77.6 %), mp 163-164 °C; MS (+)FAB m/e 318/320 (M+H+).
Elemental analysis for C16H16CIN3O2: 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 >250 °C: MS El m/e 317/319 (M+).
Elemental analysis for C16H16CIN3O2 • HCl: Calc'd: C, 54.25; H, 4.84; N, 11.86 Found: C, 54.18; H, 4.76; N, 11.87
Example 9
4-(2-Benzylamino-ethoxy)-6-chloro-l,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-(6-chloro-2-oxo-2,3-dihydro-lH-benzoimidazol-4-yloxy)-ethyl]- acetamide (5h) afforded the title compound as a white solid (77.6 %), mp 192-193 °C; MS El m/e 317/319 (M+).
Elemental analysis for C16H16CIN3O2: Calc'd: C, 60.48; H, 5.08; N, 13.22 Found: C, 60.24; H, 5.01; N, 13.09
Treatment of the free base with ethereal HCl gave the hydrochloride salt as a white solid, mp >250 °C: MS El m/e 317/319 (M+).
Elemental analysis for C16HI6ON3O2 • 1HC1: Calc'd: C, 54.25; H, 4.84; N, 11.86 Found: C, 54.23; H, 4.85; N, 11.69 Example 10
6-Chloro-4-{2-[(thiophen-2-yImethyl)-amino]-ethoxy}-l,3-dihydro- benzoimidazol-2-one
Following the general procedure used in example 1 and using N-[2-(6-chloro-2- oxo-2,3-dihydro-lH-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2- yimethyl-acetamide (5j) afforded the title compound as a white solid (89.0 %), mp 179-180 °C; MS El m/e 323/325 (M+).
Elemental analysis for C14H1 CIN3O2S: Calc'd: C, 51.93; H, 4.36; N, 12.98 Found: C, 51.80; H, 4.23; N, 12.96
Treatment of the title compound with ethereal HCl gave the hydrochloride as a white solid(90.0 %), mp >250 °C: MS El m/e 323/325 (M+).
Elemental analysis for C14H14CIN3O2S • HCl: Calc'd: C, 46.68; H, 4.20; N, 11.66 Found: C, 46.52; H, 4.00; N, 11.57
Example 11
6-Chloro-4-{2-[(thiophen-3-ylmethyI)-amino]-ethoxy}-l,3-dihydro- benzoimidazol-2-one
Following the general procedure used in example 1 and using N-[2-(6-chloro-2- oxo-2,3-dihydro-lH-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3- ylmethyl-acetamide (5j), the title compound is obtained as a white solid (89.0 %), mp 182- 183 °C; MS (+)FAB m/e 324/326 (M+H+).
Elemental analysis for Ci 4H14CIN3O2S: Calc'd: C, 51.93; H, 4.36; N, 12.98 Found: C, 51.96; H, 4.30; N, 12.95
The tide compound was treated with ethereal HCl to obtain the hydrochloride salt as a white solid (90.0% ), mp >250 °C: MS El m/e 323/325 (M+). Elemental analysis for C14H14CIN3O2S • HCl: 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-lH-isoquinolin-2yl)-ethoxy]-l,3-dihydro- benzoimidazol-2-one
Following the general procedure used in example 1 and using 2-[2-(3,4-dihydro- lH-isoquinolin-2-yl)-ethoxy]-6-nitro-phenylamine (2k) afforded the title compound as a white solid (63.0 %), mp 173-174 °C; MS El m/e 309 (M+).
Elemental analysis for C18H19N3O2: Calc'd: C, 69.88; H, 6.19; N, 13.58 Found: C, 69.48; H, 6.01; N, 13.55
Treatment of the free base with ethereal HCl gave a quarter hydrate of the hydrochloride salt as a white solid (90.0% ), mp >250 °C: MS El m/e 323/325 (M+).
Elemental analysis for C18H19N3O2 • HCl • 0.25 H2O: Calc'd: C, 61.71; H, 5.90; N, 11.99 Found: C, 61.90; H, 5.88; N, 11.97
Example 13
4-[2-(3-Phenyl-propylamine)-ethoxy]-l,3-dihydro-benzoimidazol-2-one Following the general procedures used in intermediates 4 and 5 and example 1, N-
[2-(2-amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-(3-phenyl-propyl)-acetamide (3k) afforded the title comound as a white solid; MS (+)FAB m/e 312 (M+H+).
Elemental analysis for Ci8H ιN3θ »0.5 H2O: 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 m/e 312 (M+H+).
Elemental analysis for Ci RH21N3O2 »HC1: Calc'd: C, 62.15; H, 6.38; N, 12.08
Found: C, 62.06; H, 6.21; N, 11.97
Pharmacology A method for determining intrinsic activity at the dopamine D2 receptor was recently reported [Lahti et al., Mol. Pharm., 42, 432-438, (1993)]. Intrinsic activity is predicted using die ratio of the "low-affinity agonist" (LowAg) state of the receptor and the "high-affinity agonist" (HighAg) state of the receptor, i.e. LowAg/HighAg. These ratios correlate with the agonist, partial agonist, and antagonist activities of a given compound, which activities characterize a compounds ability to elicit an antipsychotic effect. Affinity for the dopamine autoreceptor was established by a modification of the standard experimental test procedure of Seemen and Schaus, European Journal of Pharmacology 203: 105-109, 1991, wherein homogenized rat striatal brain tissue is incubated with 3H-quinpirole (Quin.) and various concentrations of test compound, filtered and washed and counted in a Betaplate scintillation counter. High affinity for the dopamine D-2 receptor was established by the standard experimental test procedure of Fields, et al., Brain Res., 136. 578 (1977) and Yamamura et al., eds., Neurotransmitter Receptor Binding, Raven Press, N.Y. (1978) wherein homogenized limbic brain tissue is incubated with 3H-spiroperidol (Spiper.) and various concentrations of test compound, filtered and washed and shaken with Hydrofluor scintillation cocktail (National Diagnostics) and counted in a Packard 460 CD scintillation counter.
The results of the tests with compounds representative of this invention are given in the immediately following table
Pharmaceutical Composition Compounds of this invention may be administered neat or with a pharmaceutical carrier to a patient in need thereof. The pharmaceutical carrier may be solid or liquid.
Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties n suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity 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 derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be as either a liquid or a solid dosage form.
The compounds of this invention may be administered rectally in the form of a conventinal suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention may be formulated into an aqueous or partrially aqueous solution, which can then be utilized in die form of an aerosol. The compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semi-solid emulsions of either the oil in water or water in oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to realease the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in d e literature.
The dosage to be used in the treatment of a specific patient suffering a dopamine imbalance must be subjectively determined by the attending physician. The variables involved include the severity of the dysfunction, and the size, age, and response pattern of the patient.
Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached. Precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with me 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 die active ingredient; the unit dosage form can be packaged compositions, for example packed powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

Claims

What is claimed:
1. A compound having the formula
wherein:
R1 is hydrogen or -Cό alkyl; R2is selected from hydrogen, straight-chain and branched -Cio alkyl, cyclohexylmethyl or -(CH2) Ar where Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from Cj-C6 alkyl, halogen, Cϊ-C6 alkoxide and trifluoromethyl; or NR'R2 is 1, 2, 3, 4-tetrahydroquinolin-l-yl or 1, 2, 3, 4-tetrahydroisoquinolin-
2-yl; m is 1-5; n is 1 or 2;
R3 is hydrogen or C,-C6 alkyl; Y is halogen, Cj-C6 alkyl, and - alkoxy; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 which is 4-(2-benzylamino-ethoxy)-l,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]-l,3- dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt tiiereof.
4. A compound according to claim 1 which is 4(7)-(2-benzylamino-ethoxy)-l-(3)-methyl- l,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 1 which is 4-(3-benzylamino-propoxy)-l,3-dihydro- benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 1 which is 4-{2-[(naphthalen-l-ylmethyl)-amino]- ethoxy}-l,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]- ed╬╣oxy}-l,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]-l,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-y╬╣methyl)- amino]-eti╬╣oxy}-l,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}-l,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-lH-isoquinolin-2yl)- ethoxy]- 1 ,3-dihydro-benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.
14. A compound according to claim 1 which is 4-(2-benzylamino-ethoxy)-l,3-dihydro- benzoimidazol-2-one or a pharmaceutically acceptable salt thereof.
15. A method of treating diseases in a mammal which respond to treatment by administration of a dopamine D agonist which comprises administration to a mammal in need tiiereof of a therapeutically effective amount of a compound according to the formula wherein:
R1 is hydrogen or Ci-Cό 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 - alkyl, halogen, Cj-C6 alkoxide and trifluoromethyl; or NR'R2 is 1, 2, 3, 4-tetrahydroquinolin-l-yl or 1, 2, 3, 4-tetrahydroisoquinolin-
2-yl; m is 1-5; n is 1 or 2;
R3 is hydrogen or C╬╗-C6 alkyl; Y is halogen, - alkyl, and Cj-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 me 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 Ci-Cό alkyl; R2is selected from hydrogen, straight-chain and branched -Cio 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 Cj-C6 alkyl, halogen, - alkoxide and trifluoromethyl; or NR'R2 is 1, 2, 3, 4-tetrahydroquinolin-l-yl or 1, 2, 3, 4-tetrahydroisoquinolin-
2-yl; m is 1-5; n is 1 or 2;
R3 is hydrogen or C╬╣~C6 alkyl; Y is halogen, - alkyl, and - alkoxy; or a pharmaceutically acceptable salt thereof.
EP98903469A 1997-02-18 1998-01-13 4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-one derivatives, their preparation and their use as dopamine autoreceptor (d2) agonists Withdrawn EP0964853A1 (en)

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