WO1998035947A1 - 4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-thiones derivatives, their preparation and their use as dopamine autoreceptor (d2) agonists - Google Patents

4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-thiones derivatives, their preparation and their use as dopamine autoreceptor (d2) agonists Download PDF

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WO1998035947A1
WO1998035947A1 PCT/US1998/000612 US9800612W WO9835947A1 WO 1998035947 A1 WO1998035947 A1 WO 1998035947A1 US 9800612 W US9800612 W US 9800612W WO 9835947 A1 WO9835947 A1 WO 9835947A1
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Prior art keywords
dihydro
ethoxy
pharmaceutically acceptable
acceptable salt
alkyl
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PCT/US1998/000612
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French (fr)
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James Albert Nelson
Richard Eric Mewshaw
Uresh Shantilal Shah
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American Home Products Corporation
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Priority to BR9807840-2A priority Critical patent/BR9807840A/en
Priority to CA002278718A priority patent/CA2278718A1/en
Priority to IL13115798A priority patent/IL131157A0/en
Priority to EP98902512A priority patent/EP0964854A1/en
Priority to HU0001942A priority patent/HUP0001942A2/en
Priority to JP53572698A priority patent/JP2001511803A/en
Priority to AU59152/98A priority patent/AU5915298A/en
Publication of WO1998035947A1 publication Critical patent/WO1998035947A1/en

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Definitions

  • This invention relates to a novel series of compounds having potency at the dopamine D 2 receptor which are illustrated by the following Formula I:
  • 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.
  • EPS extrapyramidal side effects
  • the compounds of this invention are dopamine agonists with various degrees of intrinsic activity some of which are selective autoreceptor agonists, and therefore partial agonist (i.e. activate only autoreceptors versus postsynaptic D 2 dopamine receptors).
  • partial agonist i.e. activate only autoreceptors versus postsynaptic D 2 dopamine receptors.
  • they provide functional modulation of the dopamine systems of the brain without the excessive blockade of the postsynaptic dopamine receptors which have been observed to be responsible for the serious side effects frequently exhibited by agents found otherwise clinically effective for the treatment of schizophrenia.
  • dopamine autoreceptors results in reduced neuronal firing a well as inhibition of dopamine synthesis and release and therefore provide a means of controlling hyperactivity of the dopaminergic systems.
  • the compounds of this invention were also found to have high intrinsic activity and therefore they can behave as the natural neurotransmitter, i.e., as full agonists. As such, they are useful in the treatment of diseases having abnormal concentrations of dopamine and could be used as dopamine surrogates possibly in the treatment of Parkinson's disease.
  • CGP-12177 (Ciba Geigy, shown below) was found to be a ⁇ -adrenergic receptor antagonist [J. Biol. Chem., 258, 3496- 3502, 1983].
  • the compounds of this invention are 4-aminoethoxy-l,3-dihydro-benzoimidazol-
  • R 1 is hydrogen or C ⁇ -C 6 alkyl
  • R 2 is hydrogen or Ci-C ⁇ alkyl
  • R 3 is selected from hydrogen, straight-chain and branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl or
  • -CEL mAr where Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from -C 6 alkyl, halogen, -Cg alkoxide and trifluoromethyl; or NR 2 R 3 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;
  • Y is halogen, C,-C 6 alkyl, and - alkoxy; and the pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable acid addition salts have the utility of the free base.
  • Such salts are prepared by methods well known to the art are formed with both inorganic or organic acids including but not Umited to fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene-sulfonic, hydrochloric hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
  • inorganic or organic acids including but not Umited to fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic
  • Scheme I depicts the synthesis of invention compounds where one of R 1 or R2 is hydrogen.
  • Scheme HI illustrates a route for obtaining a chlorinated intermediate which is used in the synthesis of a chlorinated invention compound.
  • the hydrochloride salt of the title compound was prepared as a white solid (90.0 %), mp >250 °C; M mle (+)FAB 340 (M+H)+.
  • the hydrochloride salt of the title compound was prepared as a white solid (90.0 %), mp >250 °C; MS mle (+)FAB 340 (M+H)+.
  • the compounds of this invention are dopamine autoreceptor agonists, that is, they serve to modulate the synthesis and release of the neurotransmitter dopamine. They are thus useful for treatment of disorders of the dopaminergic system, such as schizophrenia, Parkinson's disease and Tourette's syndrome. Such agents are partial agonists at the postsynaptic dopamine D 2 receptor and are thereby useful in the treatment of alcohol and drug addiction.
  • the compounds of this invention effect the synthesis of the neurotransmitter dopamine and thus are useful in the treatment of dopaminergic disorders such as schizophrenia, Parkinson's disease, Tourette's Syndrome, alcohol addiction, cocaine addiction, and addiction to analagous drugs.
  • Applicable solid carriers for pharmaceutical compositions containing the compounds of this invention can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintergrating agents or an encapsulating material.
  • 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 in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
  • the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols e.g. glycols
  • 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 either liquid or solid composition form.
  • 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 the active ingredient;
  • the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • the dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician.
  • the variables involved include the specific psychosis and the size, age and response pattern of the patient.

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Abstract

This invention relates to a novel series of compounds having potency at the dopamine D2 receptor which are illustrated by formula (I) wherein R1 is hydrogen or C¿1?-C6 alkyl; R?2¿ is hydrogen or C¿1?-C6 alkyl; R?3¿ is selected from hydrogen, straight-chain and branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl or -(CH¿2?)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?2R3¿ 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; Y is halogen, C¿1?-C6 alkyl, and C1-C6 alkoxy; or a pharmaceutically acceptable salt thereof.

Description

4-AMINOALKOXY-l,3-DIHYDROBENZOIMIDAZOL-2-THIONES DERIVATIVES, THEIR PREPARATION AND THEIR USE AS DOPAMINE AUTORECEPTOR (D2) AGONISTS
FIELD OF THE INVENTION
This invention relates to a novel series of compounds having potency at the dopamine D2 receptor which are illustrated by the following Formula I:
Figure imgf000003_0001
I
BACKGROUND OF INVENTION
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, 1975; and Tamminga et al., Psychiatry, 398- 402, 1986). A method for determining intrinsic activity at the dopamine D2 receptor was recently reported (Lahti et al., Mol. Pharm., 42, 432-438, 1993) Intrinsic activity is predicted using the ratio of the "low-affinity agonist" (LowAg) state of the receptor and the "high-affinity agonist" (HighAg) state of the receptor, i.e. LowAg HighAg. These ratios correlate with the agonist, partial agonist, and antagonist activities of a given compound, which activities characterize a compounds ability to elicit an antipsychotic effect.
In accordance with this invention, there is provided a group of compounds which are useful antipsychotic agents essentially free from extrapyramidal side effects (EPS). The compounds of this invention are dopamine agonists with various degrees of intrinsic activity some of which are selective autoreceptor agonists, and therefore partial agonist (i.e. activate only autoreceptors versus postsynaptic D2 dopamine receptors). As such, they provide functional modulation of the dopamine systems of the brain without the excessive blockade of the postsynaptic dopamine receptors which have been observed to be responsible for the serious side effects frequently exhibited by agents found otherwise clinically effective for the treatment of schizophrenia. Activation of the dopamine autoreceptors results in reduced neuronal firing a well as inhibition of dopamine synthesis and release and therefore provide a means of controlling hyperactivity of the dopaminergic systems. The compounds of this invention were also found to have high intrinsic activity and therefore they can behave as the natural neurotransmitter, i.e., as full agonists. As such, they are useful in the treatment of diseases having abnormal concentrations of dopamine and could be used as dopamine surrogates possibly in the treatment of Parkinson's disease.
A literature search indicated a series of benzimidazole-2-ones have been prepared as described in German Patent 2700193. In particular, CGP-12177 (Ciba Geigy, shown below) was found to be a β-adrenergic receptor antagonist [J. Biol. Chem., 258, 3496- 3502, 1983].
Figure imgf000004_0001
CGP-12177
BRIEF DESCRIPTION OF THE INVENTION The compounds of this invention are 4-aminoethoxy-l,3-dihydro-benzoimidazol-
2-thiones which are illustrated by Formula I
Figure imgf000004_0002
wherein:
R1 is hydrogen or Cι-C6 alkyl; R2 is hydrogen or Ci-Cβ alkyl; R3 is selected from hydrogen, straight-chain and branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl or
-CEL mAr where Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from -C6 alkyl, halogen, -Cg alkoxide and trifluoromethyl; or NR2R3 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;
Y is halogen, C,-C6 alkyl, and - alkoxy; and the pharmaceutically acceptable salts thereof. Pharmaceutically acceptable acid addition salts have the utility of the free base.
Such salts are prepared by methods well known to the art are formed with both inorganic or organic acids including but not Umited to fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene-sulfonic, hydrochloric hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of Formula I are generally prepared by the overall sequence indicated in the following Schemes I-III. Scheme I depicts the synthesis of invention compounds where one of R1 or R2 is hydrogen.
Scheme I
Figure imgf000006_0001
Figure imgf000006_0002
Scheme II outlines the synthesis of an inventon compound where neither of Ri and R2 are hydrogen. Scheme II
Figure imgf000007_0001
2i
Figure imgf000007_0002
Scheme HI illustrates a route for obtaining a chlorinated intermediate which is used in the synthesis of a chlorinated invention compound. Scheme HI
Figure imgf000007_0003
The following synthetic procedures for intermediates and invention products are included for illustrative purposes only and are should not be construed as limiting to this disclosure. Those skilled in the art of organic synthesis may be aware of other preparative methods for preparing the intermediates and invention compounds. The reagents and starting materials used are either commercially available or can be prepared according to standard literature procedures.
Intermediate la (n = 1)
2-(2-Chloroethoxy)-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 mle 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 mle 216/218 (M+).
Intermediate lb (n=2)
2-(3-Bromo-propoxy)-6-nitro-phenylamine
Following the procedure of method 2 above and substituting 1,3-dibromopropane for 1,2-dichloroethane, the title compound is obtained as a yellow solid, (78.7%) mp 88-89 °C; MS EI m/e 274/276 (M+). Elemental analysis for C9HnBrN2θ3: 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-nitro-phenyIamine
A mixture of 2-(2-cr_loroethoxy)-6-nitro-phenylamine (3.0 g, 13.8 mmol) and benzylamine (9.0 g, 84.0 mmol) was heated at 100-110° C for 6 hr. The excess benzylamine was removed by distillation under vacuum (70 - 75° C / 0.1 mm) . 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 mle 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
Using this general procedure and utilizing 2-(2-chloroethoxy)-6-nitro-phenylamine or 2-(3-bromo-propoxy)-6-nitro-phenylamine or 4-chloro-2-(2-chloro-ethoxy)-6-nitro- phenylamine and benzylamine, 4-methyl-benzylamine, 1-naphthalene-methylamine, 4-tert- butyl-benzylamine, thiophene-2-methyl-amine, 4-chloro-benzylamine, thiophene-3-methyl- amine or 1,2,3,4-tetrahydroisoquinoline afforded:
2b 2-[2-(4-Methyl-benzylamino)-ethoxy]-6-nitro-phenylamine as a yellow solid (89 %), mp 55-57 °C; El mle 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 mle 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-ylmethyI)-amino]-ethoxy}-6-nitro-phenylamine as a yellow solid (76.3 %), mp 66-67 °C; MS El mle 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-Butylbenzylamino)-ethoxy]-6-nitro-phenylamine as an orange viscous oil (83.3 %); MS El mle 343 (M+) which analyzed as the quarter hydrate.
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-[2-(4-Chloro-benzylamino)-ethoxy]-6-nitro-phenylamine as an orange solid (87.8 %), mp 61-62 °C; MS El mle 322/324 (M+) which analyzed as the quarter hydrate.
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
2g 2-(2-Benzylamino-ethoxy)-4-chIoro-6-nitro-phenylamine as a orange- brown colored solid (54.0 %), mp 87-88 °C; MS El mle 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 2h 4-Chloro-2-nitro-6-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy}- phenylamine as a yellow solid (44.0 %), mp 74-75 °C; MS El mle 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
2i 4-Chloro-2-nitro-6-{2-[(thiophen-3-ylmethyI)-amino]-ethoxy}- phenylamine as a yellow solid (33.3 %), mp 77-78 °C; MS El mle 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
2 2-[2-(3,4-Dihydro-lH-isoquinolin-2-yl)-ethoxy]-6-nitro-phenylamine as a yellow solid (87.1 %), mp 95-97 °C; MS El mle 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
Intermediate 3a
N-[2-(2-Amino-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide
To a solution of 2-(2-benzylamino-ethoxy)-6-nitro-phenylamine (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 mle 383 (M+).
Elemental analysis for C17H16F3N3O4:
Calc'd: C, 53.27; H, 4.21; N, 10.96 Found: C, 53.09; H, 4.35; N, 10.93. This general procedure utilizing 2-[2-(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- nitro-phenyl-amine, 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 afforded:
3b N-[2-(2-Amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifIuoro-N-(4-methyl- benzyl) acetamide as a yellow solid (79 %), mp 172-173 °C; MS El mle 397 (M+).
Elemental analysis for Cl8Hi8F3N3θ4: 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)-propyl]-N-benzyl-2,2,2-trifluoro- acetamide as a yellow solid (67.8 %), mp 92-93 °C; MS El mle 397 (M+).
Elemental analysis for C18H18F3N3O4:
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 mle 433 (M+).
Elemental analysis for C21H18F3N3O4. 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-butyI-benzyl)-
2,2,2-trifluoro-acetamide as a yellow solid (82.0 %), mp 80-82 °C; MS El mle 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]-N-(4-chloro-benzyl)-2,2,2- trifluoro-acetamide as a yellow solid (84.0 %), mp 138-139 °C; MS (+)FAB mle 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
3g N-[2-(2-Amino-5-chIoro-3-nitro-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)+.
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
3h N-[2-(2-Amino-5-chloro-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N- thiophen-2-yImethyl-acetamide as a yellow solid (59.6 %), mp 97-98 °C; MS El mle MIIAIS (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
3i N-[2-(2-Amino-5-chloro-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N- thiophen-3-ylmethyl-acetamideas a yellow solid (80.0 %), mp 149-150 °C; MS El mle 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 Intermediate 4a
N-Benzyl-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-acetarnide
To a mixture of N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro- acetamide (3a, 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 /e 354 (M+H+).
Elemental analysis for C17H1 F3N3O2: Calc'd: C, 56.58; H, 4.72; N, 12.38 Found: C, 57.49; H, 5.10; N, 11.86
This general procedure 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-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-naphthalen- 1-ylmethyl-acetamide, N-[2-(2-amino-3-nirro-phenoxy)-ethyl]-N-(4-teιt-butyl-benzyl)- 2,2,2-trifluoro-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-nitro-phenoxy)- ethyl] -2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide afforded:
4b N-[2-(2,3-Diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-(4-methyl- benzyO-acetamide as a white solid (85.0 %), mp 94-96 °C; MS El mle 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-trifluoro- acetamide as a white solid (86.5 %), mp 56-58 °C; MS El mle 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-trifIuoro-N-naphthalen-l- ylmethyl-aceta ide as a viscous yellow oil (63.0 %); MS (+)FAB mle 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 mle 409 (M+).
4f N-(4-Chloro-benzyl)-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2- trifluoro-acetamide as a brown oil (80.9 %); MS El mle 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
4g N-Benzyl-N-[2-(2,3-diamino-5-chIoro-phenoxy)-ethyI]-2,2,2- trifluoro-acetamide as a viscous brown oil (76.2 %); MS El mle 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
4h N-[2-(2,3-Diamino-5-chIoro-phenoxy)-ethyI]-2,2,2-trifluoro-N- thiophen-2-ylmethyI-acetamide as a viscous brown oil (71.4 %); MS El mle 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 4i 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 El mle 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-BenzyI-2,2,2-trifIuoro-N-[2-(2-thioxo-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 (0.57 g, 1.61 mmol) and l.l'-thiocarbonyldiimidazole (0.49 g, 3.05 mmol) in anhydrous tetrahydrofuran (30 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 (160 g silica gel, ethyl acetate) afforded 0.54 g (85.2 %) of a yellowish -colored solid. Crystallization from ethyl acetate-hexane gave a white solid, mp 158-160 °C; MS (+)FAB mle 395 (M+H)+.
Elemental analysis for C18H16F3N3O2S: Calc'd: C, 54.52; H, 3.74; N, 10.56
Found: C, 54.68; H, 4.08; N, 10.63
This general procedure 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-diarnino-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-(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 afforded: 5_b 2.2,2-TrifIuoro-N-(4-methyl-benzyI)-N-[2-(2-thioxo-2,3-dihydro- lH-benzoimidazol-4-yloxy)-ethyI]-acetamide as an off-white solid (90.9 %), mp 195-196 °C; MS El mle 409 (M+).
Elemental analysis for C 19H \ 8F3N3O2S :
Calc'd: C, 55.47; H, 4.43; N, 10.26 Found: C, 55.40; H, 4.24; N, 10.05
5c N-BenzyI-2,2,2-trifIuoro-N-[3-(2-thioxo-2,3-dihydro-lH- benzoimidazol-4-yloxy)-propyl]-acetamide as a yellow foam (99.0 %); MS El mle 409 (M+) which analyzed for a three-quarter hydrate.
Elemental analysis for C19H18F3N3O2S • 0.75 H2O: Calc'd: C, 53.96; H, 4.65; N, 10.40 Found: C, 54.05; H, 4.49; N, 10.09
5d 2,2,2-Trifluoro-N-naphthalen-l-ylmethyl-N-[2-(2-thioxo-2,3- dihydro-lH-benzoimidazol-4-yloxy)-ethyl]-acetamide as a white solid (95.0 %), mp 102-103 °C; MS El mle 445 (M+).
Elemental analysis for C22HI8F3N3O3S:
Calc'd: C, 58.73; H, 4.14; N, 9.34 Found: C, 58.84; H, 4.02; N, 9.17
5e N-(4-tert-Butyl-benzyl)-2,2,2-trifluoro-N-[2-(2-thioxo-2,3-dihydro- lH-benzoimidazol-4-yloxy)-ethyl]-acetamide as a white solid (86.4 %), mp 199- 200 °C; MS El mle 451 (M+).
Elemental analysis for C22H24F3N3O2S: Calc'd: C, 58.52; H, 5.36; N, 9.31
Found: C, 58.46; H, 5.36; N, 9.25
5f N-(4-Chloro-benzyl)-2,2,2-trifluoro-N-[2-(2-thioxo-2,3-dihydro- lH-benzoimidazoI-4-yIoxy)-ethyl]-acetamide as a white solid (72.0 %), mp 194- 196 °C; MS El mle 429/431 (M+).
Elemental analysis for C18H15CIF3N3O3S: Calc'd: C, 50.30; H, 3.52; N, 9.78 Found: C, 50.50; H, 3.54; N, 9.51
5g N-Benzyl-N-[2-(6-chloro-2-thioxo-2,3-dihydro-lH-benzoimidazol-4- yIoxy)-ethyl]-2,2,2-trifluoro-acetamide as a white solid (93.8 %), mp 201-202 °C.
Elemental analysis for C18H15CIF3N3O2S: Calc'd: C, 50.30; H, 3.52; N, 9.78 Found: C, 50.00; H, 3.40; N, 9.67
5h N-[2-(6-Chloro-2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy)- ethyl]- 2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide as a white solid (68.2 %), mp 183-184 °C; MS El mle 435/437 (M+).
Elemental analysis for C16H13CIF3N3O2S2:
Calc'd: C, 44.09; H, 3.01; N, 9.64 Found: C, 43.76; H, 2.78; N, 9.53
5i N-[2-(6-Chloro-2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy)- ethyl]- 2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide as a white solid (64.9 %), mp 179-180 °C; MS El mle 435/437 (M+).
Elemental analysis for C16H13CIF3N3O3S: Calc'd: C, 44.09; H, 3.01; N, 9.64 Found: C, 44.11; H, 2.80; N, 9.47
Intermediate 6
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- isoquinohn-2-yl)-ethoxy]-6-nitro-phenylamine (2j) 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 mle 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 7
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 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 33.5 g (95.3 %) as orange solid, mp 109-110 °C; MS El mle 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-thione
A suspension of potassium carbonate (0.90 g, 6.50 mmol) and N-benzyl-2,2,2- trifluoro-N-[2-(2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy)-ethyl]-acetamide (0.367 g, 0.928 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 crude base. Purification by chromatography (70 g silica gel, ethyl acetate : 2N NH3 in methanol, 20 : 1) afforded 0.27 g (97.2%) of a white solid. Crystallization from methanol gave white needles, mp 147-149 °C; MS mle FAB 300 (M+H+) containing methanol.
Elemental analysis for C16H17N3OS • 0.75 CH4O
Calc'd: C, 62.20; H, 6.23; N, 12.99 Found: C, 62.10; H, 6.07; N, 13.26 To a solution of 4-(2-benzylamino-ethoxy)-l,3-dihydro-benzoimidazole-2-thione (0.195 g, 0.65 mmol) in methanol (40 mL) was added an excess of IN hydrogen chloride in ether to afford 0.155 g (67.4 %) of the hydrochloride salt monohydrate of the title compound as white solid, mp 253-255 °C; MS mle (+)FAB 300 (M+H+).
Elemental analysis for C16H17N3OS • HCl • H2O: Calc'd: C, 54.31; H, 5.70; N, 11.87 Found: C, 54.62; H, 5.48; N, 12.00
Example 2
4-[2-(4-Methyl-benzylamino)-ethoxy]-l,3-dihydro-benzoimidazole-2-thione
The general procedure used in example 1 and utilizing 2,2,2-trifluoro-N-(4-methyl- benzyl)-N-[2-(2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy)-ethyl]-acetamide (5b) afforded:
4-[2-(Methyl-benzylamino)-ethoxy)]- 1 ,3-dihydro-benzoimidazole-2-thione as a white solid quarter hydrate (97.2 %), mp 154-156 °C; MS mle El 313 (M+).
Elemental analysis for C17H19N3OS • 0.25 H2O: Calc'd: C, 64.23; H, 6.18; N, 13.22 Found: C, 64.37; H, 5.93; N, 13.07.
Addition of excess IN hydrogen chloride in ether gave 4-[2-(4-Methyl- benzyl_ ιino)-ethoxy]-l,3-dihydro-benzoimidazole-2-thione • HCl • hydrate as a white solid (71.1 %), mp > 250 °C; MS mle (+)FAB 314 (M+H)+.
Elemental analysis for C17H19N3OS • HCl • H2O Calc'd: C, 55.50; H, 6.03; N, 11.42 Found: C, 55.81; H, 5.79; N, 11.33 Example 3
4-(2-Benzylamino-propoxy)-l,3-dihydro-benzoimidazole-2-thione
The general procedure used in example 1 and utilizing N-benzyl-2,2,2-trifluoro-N-
[3-(2-thioxo-2,3-dihydro-lH-benzoimidazole-4-yloxy)-propyl]-acetamide (5c) afforded:
4-(2-Benzylamino-propoxy)- 1 ,3-dihydro-benzoimidazole-2-thione as a white solid (64.4 %), mp 203-204 °C; MS mle El 313 (M+).
Elemental analysis for C17H19N3OS • 0.25 H2O: Calc'd: C, 64.23; H, 6.18; N, 13.22 Found: C, 64.10; H, 5.08; N, 12.84
Addition of excess IN hydrogen chloride in ether gave the hydrochloride salt quarter hydrate of 4-(2-Benzylamino-propoxy)-l,3-dihydro-benzoimidazole-2-thione as a white solid (92.5 %), mp 243-244 °C; MS mle El 313 (M)+.
Elemental analysis for C17H19N3OS • HCl • 0.25 H2O Calc'd: C, 57.62; H, 5.83; N, 11.86
Found: C, 57.58; H, 5.71; N, 11.72
Example 4
4-{2-[(Naphthalen-l-ylmethyI)-arnino]-ethoxy}-l,3-dihydro- benzoimidazole-2-thione
The general procedure used in example 1 and utilizing 2,2,2-trifluoro-N- naphthalen-l-ylmethyl-N-[2-(2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy)-ethyl]- acetamide (5d) afforded:
4- { 2-[(Naphthalen- 1 -ylmethyl)-amino]-ethoxy } - 1 ,3-dihydro-benzoimidazole-2- thione • 0.5 ethyl acetate as a white solid (66.6 %), mp 191-193 °C; MS mle El 349 (M+).
Elemental analysis for C20H19N3OS • 0.5 C4H8O2: Calc'd: C, 67.15; H, 5.89; N, 10.68 Found: C, 66.97; H, 5.75; N, 10.76
Addition of excess IN hydrogen chloride in ether to the above product gave the three quarters hydrated hydrochloride salt of the title as a white solid (90.0 %), mp 240- 242 °C; MS mle El 349 (M)+.
Elemental analysis for C20H19N3OS • HCl • 0.75 H2O Calc'd: C, 60.14; H, 5.43; N, 10.52 Found: C, 60.42; H, 5.48; N, 10.09
Example 5
4-[2-(4-tert-Butyl-benzylamino)-ethoxy]-l,3-dihydro-benzoimidazole-2- thione
The general procedure used in example 1 and utilizing N-(4-tert-butyl-benzyl)- 2,2,2-trifluoro-N-[2-(2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy)-ethyl]-acetamide (5e) afforded:
4-[2-(4-tert-Butyl-benzylamino)-ethoxy]- l,3-dihydro-benzoimidazole-2-thione as a white solid (79.3 %), mp 125-127 °C; MS mle El 355 (M+).
Elemental analysis for C20H25N3OS: Calc'd: C, 67.57; H, 7.09; N, 11.82
Found: C, 67.02; H, 7.00; N, 11.67
Treatment of the above free base with excess IN hydrogen chloride in ether gave the one-quarter hydrate of the hydrochloride salt of the title compound as a white solid (90.0 %), mp >250 °C; MS mle El 355 (M)+.
Elemental analysis for C20H25N3OS • HCl • 0.25 H2O: Calc'd: C, 60.59; H, 6.74; N, 10.60 Found: C, 60.50; H, 5.68; N, 10.44 Example 6
4-[2-(4-Chloro-benzylamino)-ethoxy]-l,3-dihydro-benzoimidazole-2-thione
The general procedure used in example 1 and utilizing N-(4-Chloro-benzyl)-2,2,2- trifluoro-N-[2-(2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy)-ethyl]-acetamide (5f) afforded:
4-[2-(4-Chloro-benzylamino)-ethoxy]-l,3-dihydro-benzoimidazole-2-thione as a white solid (85.9 %), mp 160-162 °C; MS mle (+)FAB 334/336 (M+H+).
Elemental analysis for C16H16CIN3OS: Calc'd: C, 57.57; H, 4.83; N, 12.59 Found: C, 57.17; H, 4.64; N, 12.35
Treatment with excess IN hydrogen chloride in ether gave the hydrochloride salt of the title compound as a white solid (90.0 %), mp 204-205 °C; MS mle El 333/335 (M)+.
Elemental analysis for CI6H16N3OS • HCl: Calc'd: C, 51.90; H, 4.63; N, 11.35
Found: C, 51.86; H, 4.46; N, 11.22
Example 7
4-(2-Benzylamino-ethoxy)-6-chloro-l,3-dihydro-benzoimidazole-2-thione
The general procedure used in example 1 and utilizing N-benzyl-N-[2-(6-chloro-2- tr_ioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-acetamide (5g) afforded:
4-(2-Benzylamino-ethoxy)-6-chloro- l,3-dihydro-benzoimidazole-2-thione as a white solid (88.2 %), mp 234-237° C; MS mle El 333/335 (M+).
Elemental analysis for C16H16CIN3OS • 0.4 H2O:
Calc'd: C, 56.35; H, 4.97; N, 12.32 Found: C, 56.43; H, 4.76; N, 12.26 Reaction of the above prepared compound with excess IN hydrogen chloride in ether gave 4-(2-Benzylamino-ethoxy)-6-chloro- 1 ,3-dihydro-benzoimidazole-2-thione»HCl as a white solid (95.0 %), mp >250 °C; MS mle El 333/335 (M+).
Elemental analysis for C16H16CIN3OS • HCl: Calc'd: C, 51.90; H, 4.63; N, 11.35 Found: C, 51.79; H, 4.62; N, 11.20
Example 8
6-Chloro-4-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy}-l,3-dihydro- benzoimidazole-2-thione
The general procedure used in example 1 and utilizing N-[2-(6-chloro-2-thioxo- 2,3-dihydro-lH-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl- acetamide (5h) afforded:
6-Chloro-4- { 2-[(thiophen-2-ylmethyl)-amino]-ethoxy } - 1 ,3-dihydro- benzoimidazole-2-thione • hemihydrate as a white solid (92.0 %), mp 183-184 °C; MS mle El 339/341 (M+).
Elemental analysis for C14H14CIN3OS3 • 0.5 H2O: Calc'd: C, 48.20; H, 4.33; N, 12.04
Found: C, 48.30; H, 3.99; N, 11.91
The hydrochloride salt of the title compound was prepared as a white solid (90.0 %), mp >250 °C; M mle (+)FAB 340 (M+H)+.
Elemental analysis for C14H14CIN3OS3 • HCl: Calc'd: C, 44.68; H, 4.02; N, 11.17 Found: C, 44.28; H, 3.87; N, 10.83 Example 9
6-Chloro-4-{2-[(thiophen-3-ylmethyl)-amino]-ethoxy}-l,3-dihydro- benzoimidazole-2-thione The general procedure used in example 1 and utilizing N-[2-(6-chloro-2-thioxo-
2,3-dihydro-lH-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl- acetamide (5i) afforded:
6-Chloro-4- { 2-[(thiophen-3-ylmethyl)-amino]-ethoxy } - 1 ,3-dihydro- benzoimidazole-2-thione as a white solid (77.0 %), mp 197-198 °C; MS mle (+)FAB 340/342 (M+H+).
Elemental analysis for C14H14CIN3OS3: Calc'd: C, 49.48; H, 4.15; N, 12.36 Found: C, 49.27; H, 4.14; N, 12.30
The hydrochloride salt of the title compound was prepared as a white solid (90.0 %), mp >250 °C; MS mle (+)FAB 340 (M+H)+.
Elemental analysis for C14H14CIN3OS3 • HCl:
Calc'd: C, 44.68; H, 4.02; N, 11.17 Found: C, 44.28; H, 3.87; N, 10.83
Example 10
4-[2-(3,4-Dihydro-lH-isoquinolin-2-yl)-ethoxy]-l,3-dihydro- benzoimidazole-2-thione
Following the general procedure used in example 1 and utilizing 2-[2-(3,4-dihydro- lH-isoquinolin-2-yl)-ethoxy]-6-nitro-phenylamine (2j) afforded the title compound as a yellow solid (60.0 %), mp 249-250 °C; MS mle El 325 (M+).
Elemental analysis for C18H19N3OS: Calc'd: C, 66.43; H, 5.88; N, 12.91
Found: C, 66.07; H, 5.92; N, 12.85 The hydrochloride salt of the title compound was prepared as a light yellow solid (90.0 %), mp 213-214 °C; MS mle El 325 (M)+.
Elemental analysis for C16H16CIN3OS • HCl: Calc'd: C, 59.74; H, 5.57; N, 11.61
Found: C, 59.12; H, 5.52; N, 11.50
PHARMACOLOGY The compounds of this invention are dopamine autoreceptor agonists, that is, they serve to modulate the synthesis and release of the neurotransmitter dopamine. They are thus useful for treatment of disorders of the dopaminergic system, such as schizophrenia, Parkinson's disease and Tourette's syndrome. Such agents are partial agonists at the postsynaptic dopamine D2 receptor and are thereby useful in the treatment of alcohol and drug addiction.
Affinity for the dopamine autoreceptor was established by a modification of the standard experimental test procedure of Seemen and Schaus, European Journal of
Pharmacology 203: 105-109, 1991, wherein homogenized rat striatal brain tissue is incubated with 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 following table.
Figure imgf000027_0001
Hence, the compounds of this invention effect the synthesis of the neurotransmitter dopamine and thus are useful in the treatment of dopaminergic disorders such as schizophrenia, Parkinson's disease, Tourette's Syndrome, alcohol addiction, cocaine addiction, and addiction to analagous drugs.
Applicable solid carriers for pharmaceutical compositions containing the compounds of this invention can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintergrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
The dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician. The variables involved include the specific psychosis and the size, age and response pattern of the patient.

Claims

WHAT IS CLAIMED IS:
( 1 ) A compound of the formula:
Figure imgf000029_0001
I
wherein:
R1 is hydrogen or Cι-C6 alkyl; R2 is hydrogen or Cι-C6 alkyl;
R3 is selected from hydrogen, straight-chain and branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl or
-CH^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, Cj-C6 alkoxide and trifluoromethyl; or NR R3 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; Y is halogen, - alkyl, and - alkoxy; or a pharmaceutically acceptable salt thereof.
(2) A compound according to claim 1 wherein Ri or R2 is benzyl, substituted benzyl, thienylmethyl, furanylmethyl, phenybutyl, cyclohexylmethyl, or 4-fluorobutyrophenone.
(3) A compound according to claim 1 which is 4-(2-benzylamino-ethoxy)-l,3-dihydro- benzoimidazole-2-thione or a pharmaceutically acceptable salt thereof.
(4) A compound according to claim 1 which is 4-[2-(4-methyl-benzyl)-amino-ethoxy]- l,3-dihydro-benzoimidazole-2-thione or a pharmaceutically acceptable salt thereof.
(5) A compound according to claim 1 which is 4-(2-benzylamino-propoxy)-l,3- dihydro-benzoimidazole-2-thione 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-benzoimidazole-2-thione or a pharmaceutically acceptable salt thereof.
(7) A compound according to claim 1 which is 4-[2-(4-tert-butyl-benzylamino)- ethoxy]-l,3-dihydro-benzoimidazole-2-thione or a pharmaceutically acceptable salt thereof.
(8) A compound according to claim 1 which is 4-[2-(4-chloro-benzylamino)-ethoxy]- l,3-dihydro-benzoimidazole-2-thione or a pharmaceutically acceptable salt thereof.
(9) A compound according to claim 1 which is 4-(2-benzylamino-ethoxy)-6-chloro- l,3-dihydro-benzoimidazole-2-thione or a pharmaceutically acceptable salt thereof.
(10) A compound according to claim 1 which is 6-chloro-4-{2-[(thiophen-2-ylmethyl)- amino]-ethoxy } - 1 ,3-dihydro-benzoimidazole-2-thione or a pharmaceutically acceptable salt thereof.
(11) A compound according to claim 1 which is 6-chloro-4-{2-[(thiophen-3-ylmethyl)- amino]-ethoxy}-l,3-dihydro-benzoimidazole-2-thione or a pharmaceutically acceptable salt thereof.
(12) A compound according to claim 1 which is 4-[2-(3,4-Dihydro-lH-isoquinolin-2- yl)-ethoxy]-l,3-dihydro-benzoimidazole-2-thione or a pharmaceutically acceptable salt thereof.
(13) A compound according to claim 1 which is or a pharmaceutically acceptable salt thereof.
(14) A method of treating diseases in a mammal that respond to treatment with a dopamine D2 agonist which comprises administration to a mammal in need thereof a therapeutically effective amount of a compound of the formula
Figure imgf000030_0001
I wherein:
R1 is hydrogen or Cι-C6 alkyl;
R2 is hydrogen or Cι-C6 alkyl; R3 is selected from hydrogen, straight-chain and branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl or
-CH^mAr where Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from C,-C6 alkyl, halogen, -C8 alkoxide and trifluoromethyl; or NR2R3 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;
Y is halogen, - alkyl, and - alkoxy; or a pharmaceutically acceptable salt thereof.
(15) The method according to claim 4 wherein the disease treated is schizophrenia.
(16) The method according to claim 4 wherein the disease treated is Tourette' s syndrome.
(17) The method according to claim 4 wherein the disease treated Parkinson's disease.
(18) The method according to claim 4 wherein the disease treated is drug or alcohol addiction..
(19) A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the formula
Figure imgf000031_0001
I
wherein:
R1 is hydrogen or Cι-C6 alkyl; R2 is hydrogen or Cι-C6 alkyl; R3 is selected from hydrogen, straight-chain and branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl or -CH^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, Cj-C6 alkoxide and trifluoromethyl; or NR2R3 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;
Y is halogen, - alkyl, and C,-C6 alkoxy; rmaceutically acceptable salt thereof.
PCT/US1998/000612 1997-02-18 1998-01-13 4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-thiones derivatives, their preparation and their use as dopamine autoreceptor (d2) agonists WO1998035947A1 (en)

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CA002278718A CA2278718A1 (en) 1997-02-18 1998-01-13 4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-thiones derivatives, their preparation and their use as dopamine autoreceptor (d2) agonists
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986001204A1 (en) * 1984-08-15 1986-02-27 Schering Aktiengesellschaft New dopamine derivatives, process for their production, and their use as medicinal products
EP0707007A1 (en) * 1994-10-14 1996-04-17 MERCK PATENT GmbH Amino(thio)ether derivatives as CNS active agents
WO1997023216A1 (en) * 1995-12-22 1997-07-03 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective nmda receptor antagonists

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986001204A1 (en) * 1984-08-15 1986-02-27 Schering Aktiengesellschaft New dopamine derivatives, process for their production, and their use as medicinal products
EP0707007A1 (en) * 1994-10-14 1996-04-17 MERCK PATENT GmbH Amino(thio)ether derivatives as CNS active agents
WO1997023216A1 (en) * 1995-12-22 1997-07-03 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective nmda receptor antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JAEN J.C. ET AL.: "Dopamine autoreceptor agonists as potential antipsychotics. 1. (Aminoalkoxy)anilines", JOURNAL OF MEDICINAL CHEMISTRY, vol. 31, no. 8, August 1988 (1988-08-01), pages 1621 - 1625, XP000674393 *

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