JP2001512458A - 4-aminoethoxyindazole derivative - Google Patents

Abstract

(57) The present invention provides a compound of the formula (I): Wherein Y is hydrogen, halogen or C ₁ -C ₆ alkoxy; R ¹ is hydrogen or C ₁ -C ₆ alkyl; X is methylene, oxygen or carbonyl; Ar is phenyl or thienyl; Is optionally substituted with one to two groups independently selected from C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, halogen, trifluoromethyl and phenyl; n = 0 or represented by to 4], or to dopamine D ₂ agonist is a pharmaceutically acceptable salt thereof. Dopamine D ₂ agonist, schizophrenia, are useful in the treatment of Tourette's syndrome, drug and alcohol addiction, also useful for the treatment of Parkinson's disease.

Description

DETAILED DESCRIPTION OF THE INVENTION                   4-aminoethoxyindazole derivatives                                Field of the invention   The present invention provides dopamine D useful for antipsychotic effects and antiparkinson's disease._TwoAgonist The present invention relates to 4-aminoethoxyindazole derivatives having activity.                                Background of the Invention   Successful attempts to induce antipsychotic activity using dopamine autoreceptor agonists (Dorsini et al., Advances in Biochemical Psychopher -Machology (Adv. Biochem. Psychopharmacol.), 16, 645-648, 1977; mminga) et al., Science, 200, 567-568, 1975; and Taminga (Tamminga). ) Et al., Psychiatry, 398-402, 1986). Recently, dopamine D_TwoTo the receptor A method for measuring intrinsic activity in mice was reported [Lahti et al., Molecular -Pharmacology (Mol. Pharm.), 42, 432-438, 1993]. The intrinsic activity of this receptor "Low-affinity agonist" (low Ag) status and the "high-affinity agonist" (high A g) As expected using state ratio, ie low Ag / high Ag. These ratios are Correlate with the agonist, partial agonist and antagonist activity of a given compound. Thus, such activity characterizes the compound's ability to elicit an antipsychotic effect. Of the present invention The compounds are dopamine agonists with various intrinsic activities, some of which are Is a selective autoreceptor agonist and therefore a partial agonist (i.e. , Post-synaptic dopamine D_TwoActivates only autoreceptors for the receptor). But Thus, they have been found to be clinically effective in treating schizophrenia Drugs identified as the cause of serious side effects often exhibited by drugs Modulates the function of the brain dopamine system without excessively blocking dopamine receptors give. Activation of dopamine autoreceptors can only be achieved by inhibiting dopamine synthesis and release. No neuronal excitement, and thus, inhibits hyperactivity of the dopamine system Give them the means to control. The compounds of the invention have also been found to have high intrinsic activity. Re And therefore they are natural neurotransmitters, i.e. full agonists Can function as Therefore, they can be used for diseases with abnormal dopamine levels. Useful for the treatment of disease, and probably dopamine substitution in the treatment of Parkinson's disease Could be used as medicine. In addition, the compounds of the invention are essentially pyramidal. No extracorporeal side effects (EPS).                                Summary of the Invention   The compounds of the present invention have the following formula I: [Where,   Y is hydrogen, halogen or C₁-C₆Alkoxy;   R¹Is hydrogen or C₁-C₆Alkyl;   X is methylene, oxygen or carbonyl;   Ar is phenyl or thienyl, each optionally with C₁-C₆Al Coxy, C₁-C₆From alkyl, halogen, trifluoromethyl and phenyl Optionally substituted with one or two independently selected groups;   n = 0-4] Is a 4-aminoethoxy-benzimidazole derivative.   The compound of formula I is a pharmaceutically acceptable acid having the utility of a free base. It may be used in the form of an addition salt. Such salts are prepared according to methods known in the art. Inorganic or organic acids (e.g., fumaric acid, maleic acid, benzoic acid, Vinic acid, pamoic acid, succinic acid, bismethylene salicylic acid, methanesulfonic acid, eta Disulfonic acid, acetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid Acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspa Laginic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-amido Benzoic acid, glutamic acid, benzene-sulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, (Cyclohexylsulfamic acid, phosphoric acid and nitric acid). It is.   Compounds of formula I are generally prepared by all routes shown in Scheme I below. Is done.                                Scheme I   The following examples relating to the preparation of intermediates and compounds of the present invention are intended to be illustrative. Included as an intent to limit this disclosure in any way Should not be interpreted. Those skilled in the art of organic synthesis will appreciate further May be aware of the synthetic route of The reagents and intermediates used here are Commercially available, or prepared according to standard literature procedures. It is.                                 Intermediate 1            1- (2-chloroethoxy) -2-methyl-3-nitrobenzene   2-Methyl-3-nitro-phenol in anhydrous tetrahydrofuran (70 mL) (3.0 g, 19.6 mmol), triphenylphosphine (7.2 g, 27.4 mmol) Solution) and chloroethanol (1.89 g, 23.5 mmol) in diethyl. A solution of luazide dicarboxylate (4.78 g, 27.4 mmol) was added slowly. Was. After 1 hour, the reaction was completed, the solvent was removed, and the residue was washed with 1: 1 ethyl acetate-hexane. Dissolved in sun (150 mL). After 30 minutes, the solid triphenylphosphine oxide The side was filtered and the solvent was removed again. The crude product is chromatographed (20% vinegar (Ethyl acetate-hexane) to give 4.2 g (100%) of a light yellow solid. . 58-59 ° C.   Elemental analysis results (C₉H_TenClNO_ThreeAs):   Calculated: C, 50.13; H, 4.68; N, 6.50.   Found: C, 50.15; H, 4.66; N, 6.47.                                 Intermediate 2            1- (2-chloroethoxy) -2-methyl-3-aminobenzene   In ethanol (200 mL) containing 500 mg of 5% palladium / carbon 1- (2-chloroethoxy) -2-methyl-3-nitrobenzene (10.7 g, 50 mm Mol) was hydrogenated at 50 psi for 4 hours. The catalyst was used for Solka Flock. loc) and the solvent was removed in vacuo to give 9.1 g (98.8%) of a yellow oil. Was.                                 Intermediate 3             1-acetyl-4- (2-chloroethoxy) -indazole   1- (2-chloroethoxy) -2-methyl-3-aminobenzene (9.0 g, 48.6 mm Mol), acetic anhydride (15.4 mL, 163 mmol) and potassium acetate (5.0 g, 51 mmol) at 80 ° C. with isoamyl nitrite (10 mL, 75 mmol). ) Was added dropwise. The reaction was stirred at 80 ° C. for 18 hours, then cooled to room temperature and filtered. I have. The solvent was concentrated. As a result, a solid is formed. This is filtered and And obtain 9.3 g (79.5%) of a yellow solid. 77-79 ° C; I R (KBr) 1710cm^-1MS EI m / e 238/240 (M⁺);   Elemental analysis results (C₁₁H₁₁ClN_TwoO_ThreeAs):   Calculated: C, 55.36; H, 4.65; N, 11.74.   Found: C, 55.17; H, 4.52; N, 11.40.                                 Example 1       Benzyl- [2- (1H-indazol-4-yloxy) -ethyl] -amine   1-acetyl-4- (2-chloro) in anhydrous dimethylsulfoxide (10 mL) Ethoxy) -indazole (1.0 g, 4.2 mmol) and benzylamine (1.8 g, 16.8 mmol) was heated to 100 ° C. for 18 hours. This reactant is Diluted with ter (100 mL), washed with 10% aqueous sodium carbonate solution and brine, Dry over magnesium sulfate, filter and remove the solvent. Chromatography (3% methanol-methylene chloride), 600 mg (53%) of a yellow solid I got 107-108 ° C. Oxalate in ethanol as a white solid Prepared. 220-221 ° C.   Elemental analysis results (C₁₆H₁₇N_ThreeOC_TwoH_TwoO_FourAs):   Calculated: C, 60.50; H, 5.36; N, 11.76.   Found: C, 60.23; H, 5.23; N, 11.62.                                 Example 2              [2- (1H-indazol-4-yloxy) -ethyl]-                     Thiophene-2-ylmethyl-amine   According to the general procedure of Example 1, 2-thiophene-methyl was used instead of benzylamine. Using luamine, the title compound was obtained with a yield of 87%. Is this compound ethanol? Isolated as oxalate. 220-221 ° C (decomposition).   Elemental analysis results (C₁₄H_FifteenN_ThreeOS ・ C_TwoH_TwoO_FourAs):   Calculated: C, 52.84; H, 4.71; N, 11.55.   Found: C, 52.72; H, 4.61; N, 11.55.                                 Example 3              [2- (1H-indazol-4-yloxy) -ethyl]-                      Thiophene-3-ylmethyl-amine   According to the general procedure of Example 1, 2-thiophene-methyl was used instead of benzylamine. Using luamine, the title compound was obtained with a yield of 87%. Is this compound ethanol? Isolated as oxalate. Melting point 215-216 [deg.] C.   Elemental analysis results (C₁₄H_FifteenN_ThreeOS ・ C_TwoH_TwoO_FourAs):   Calculated: C, 52.84; H, 4.71; N, 11.55.   Found: C, 52.72; H, 4.61; N, 11.37.                                  Pharmacology   The compounds of the present invention are dopamine autoreceptor agonists. That is, they Helps regulate the synthesis and release of the nervous system transmitter dopamine. Thus, These include disorders of the dopamine system such as schizophrenia, Parkinson's disease and It is useful for treating Rett syndrome and the like. Such drugs include post-synaptic dopamine D_Two Is a partial agonist at the receptor and is therefore Useful for treatment.   The affinity for dopamine autoreceptors was determined by Seemen and Schaus aus), European Journal of Pharmacology (European Journal of Pharmacology), 203, 105-109, 1991. . In this method, homogenized rat striatal brain tissue is^ThreeH-Quinpyrrole (Quin. ) And various concentrations of the test compound, filtered, washed, and Count on a Betaplate scintillation counter.   Dopamine D_TwoThe high affinity for the receptor is described by Fields et al., Brain et al. Research (Brain Res.), 136,578 (1977) and edited by Yamamura et al., NeuroTransmi Neurotransmitter Receptor Binding, Established by Raven Press, N.Y. (1978), a standard experimental test method. Was. In this method, homogenized limbic brain tissue is^ThreeH-spiroperidol (Spiper.) And with various concentrations of the test compound, filtered, washed, and Hydrofluor scintillation cocktail (National Diamond) Shake with Gnostics (National Diagnostics), Packard 46 Count with a 0CD scintillation counter.   The results of tests using representative compounds of the present invention are shown in the table below.   Thus, the compounds of the present invention effect the synthesis of the nervous system transmitter dopamine, thus Schizophrenia, Parkinson's disease, Tourette's syndrome, alcohol addiction, Useful for treatment of dopamine disorders such as Cain addiction and addiction to similar drugs It is.                                Pharmaceutical composition   Solid carriers applicable to pharmaceutical compositions containing the compound of the present invention include flavoring agents , Lubricants, solubilizers, suspending agents, fillers, fluidizers, compression aids, binders or tablets One or more substances or encapsulating materials that can also act as disintegrants Can be mentioned. In powders, the carrier is a finely divided solid, It is mixed with finely ground active ingredient. For tablets, the active ingredient It is mixed with a carrier having the necessary compression properties in an appropriate ratio and pressed to the desired shape and size. Shrink molded. The powders and tablets preferably contain up to 99% of the active ingredient. You. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate. Cium, talc, sugar, lactose, dextrin, starch, gelatin, cellulose , Methylcellulose, sodium carboxymethylcellulose, polyvinylpyro Lysine, low melting waxes and ion exchange resins.   Liquid carriers form solutions, suspensions, emulsions, syrups and elixirs It may be used for The active ingredient of the present invention may be water, an organic solvent, a mixture of both, or a medicament. Dissolving or suspending in a pharmaceutically acceptable liquid carrier such as a pharmaceutically acceptable fat or oil Can be. Liquid carriers include solubilizers, emulsifiers, buffering agents, preservatives, sweeteners, flavoring agents , Suspending agents, thickeners, coloring agents, viscosity regulators, stabilizers or osmotic pressure regulators Can be included. Liquid for oral and parenteral administration Suitable examples of the carrier include water (particularly an additive as described above (e.g., cellulose-derived Body, preferably sodium carboxymethylcellulose solution)), Coal (including monohydric and polyhydric alcohols (e.g., glycols)) And their derivatives, and oils such as fractionated coconut and peanut oils. You. For parenteral administration, carriers include ethyl oleate and isopromyristate. It can also be an oily ester such as a pill. Sterile liquid carrier for parenteral administration Used in sterile liquid compositions.   Liquid pharmaceutical compositions that are sterile solutions or suspensions can be, for example, intramuscular, intraperitoneal or intramuscular. Alternatively, it can be used by subcutaneous injection. Sterile solutions should be administered intravenously. Can also be. Oral administration can be in either liquid or solid composition form .   The pharmaceutical composition is preferably in unit dosage form (eg, a tablet or capsule). Good. In such form, the composition is administered in unit dosage form containing an appropriate amount of the active ingredient. Subdivided into quantities. The unit dosage form can contain the packaged composition (e.g., , Ampules, filled syringes or liquid-containing medicine bags). Unit agent The form can be, for example, a capsule or tablet itself, or Such compositions can be in any number of packaging forms.   The dose to be used in the treatment of a particular mental illness must be subjectively determined by the attending physician. Must. Relevant variables include specific mental illness and patient physique, age and And response patterns.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) C07D 409/12 C07D 409/12 (81) Designated country EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, U, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL , PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW

Claims (1)

[Claims] 1. formula: Wherein Y is hydrogen, halogen or C ₁ -C ₆ alkoxy; R ¹ is hydrogen or C ₁ -C ₆ alkyl; X is methylene, oxygen or carbonyl; Ar is phenyl or thienyl; Is optionally substituted with one or two groups independently selected from C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, halogen, trifluoromethyl and phenyl; n = 0 Or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which is benzyl- [2- (1H-indazol-4-yloxy) -ethyl] -amine, or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, which is [2- (1H-indazol-4-yloxy) -ethyl] -thiophen-2-ylmethyl-amine, or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1, which is [2- (1H-indazol-4-yloxy) -ethyl] -thiophen-3-ylmethyl-amine, or a pharmaceutically acceptable salt thereof. 5. A method of treating a disorder in a mammal that is responsive to treatment with the dopamine D ₂ agonist, the mammal in need of such treatment a therapeutically effective amount of a compound of formula: Wherein Y is hydrogen, halogen or C ₁ -C ₆ alkoxy; R ¹ is hydrogen or C ₁ -C ₆ alkyl; X is methylene, oxygen or carbonyl; Ar is phenyl or thienyl; Is optionally substituted with one or two groups independently selected from C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, halogen, trifluoromethyl and phenyl; n = 0 ~ 4] or a pharmaceutically acceptable salt thereof. 6. 6. The method according to claim 5, wherein the disease to be treated is schizophrenia. 7. 6. The method according to claim 5, wherein the disease to be treated is Parkinson's disease. 8. 6. The method according to claim 5, wherein the disease to be treated is Tourette's syndrome. 9. The method according to claim 5, wherein the disease to be treated is drug addiction or alcohol addiction. 10. A pharmaceutically acceptable carrier and a therapeutically effective amount of the formula: Wherein Y is hydrogen, halogen or C ₁ -C ₆ alkoxy; R ¹ is hydrogen or C ₁ -C ₆ alkyl; X is methylene, oxygen or carbonyl; Ar is phenyl or thienyl; Is optionally substituted with one or two groups independently selected from C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, halogen, trifluoromethyl and phenyl; n = 0 Or a pharmaceutically acceptable salt thereof.