JP2002513001A - Antipsychotic indolyl derivatives - Google Patents

Abstract

(57) [Summary] The present invention provides a compound represented by the general formula (1): [Wherein R ₁ and R ₂ are H, OH, F, Cl, Br, I, alkyl or alkenyl having 1 to 6 carbons, alkoxy, aryl having 1 to 6 carbons, OR ₅ , nitro, amino or CF ₃ or R ₁ and R ₂ together form a fused ring at the 1,2- or 2,3-position to form a fused phenyl or benzodioxane group, or 4- Or a 7-substituted indole group, or a 4- or 5- or 8-substituted quinoline group; R ₃ is a group selected from hydrogen, alkyl having 1 to 6 carbons, alkoxy having 1 to 4 carbons or halogen the expressed; R ₄ is hydrogen, a group selected from alkyl or R ₅ having 1 to 6 carbon atoms; R ₅ is CH ₂ Ph, wherein the phenyl ring is optionally, OMe, halogen or CF ₃ Substituted with a group selected from Can have; X is, N, CR _4, is selected from the groups represented by CHR ₄ and CHCH; A is, N, NH, is selected from the group represented by CH and CH _2; B is, = O , = S, H and H ₂ ; or A and B may be linked together to form an indole, benzimidazole, indolone or indoline moiety] Provided are compounds or pharmaceutically acceptable salts thereof, and pharmaceutical compositions and methods for treating central nervous system disorders using these compounds.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] This application is based on a petition filed on April 29, 1998, pursuant to a petition filed under 37 CFR 1.53 (c) (2) (i). Claim the benefit of U.S. Provisional Application No. 60 / 104,596, which is adapted from 09 / 069,129.

[0002] The present invention relates to a series of novel β-pharmaceuticals that are effective medicaments for the treatment of conditions associated with or affected by the dopamine D ₂ receptor and serotonin 1A receptor subtypes.
-Hydroxyaryloxypropylamine. These compounds are particularly useful for the treatment of schizophrenia and related psychiatric disorders and other conditions, such as Parkinson's disease and Alzheimer's disease.

[0003] In their letter to the editors [TINS, Vol. 17, No. 4, 1994],
Bowen et al. Show that the recognition-conferring properties of Alzheimer's disease can be improved by antagonists at the inhibitory 5-HT _1A receptor or by activation of phospholipase-C-linked choline M ₁ receptor. ing.

SUMMARY OF THE INVENTION The present invention relates to novel indolyl derivatives, processes for their preparation, pharmaceutical compositions containing them, and their use in therapy. Such compounds include dopamine D ₂
Their ability to antagonize at the receptors is useful in treating psychiatric disorders, especially schizophrenia. In addition, the present invention also provides compounds that are antagonists and agonists at the 5-HT _1A receptor subtype, and thus the compounds of the present invention are useful for treating Alzheimer's disease, Parkinson's disease, depression and anxiety. Can be used.

The compounds of the present invention have the general formula (I):

[0006]

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[Wherein, R ₁ and R ₂ each independently represent H, OH, F, Cl, Br, I, carbon number 1 to
6 alkyl or alkenyl, C 1-6 alkoxy, aryl, arylalkyl, aralkyloxy, OR ₅ , nitro, amino or CF ₃ , and R ₁ and R ₂ when taken together are 1 Form a fused ring at the 2,2- or 2,3-position to give a fused phenyl or benzodioxane group, or a 4- or 7-substituted indole group, or a 4- or 5- or 8-substituted quinoline group , The substituent on the indole or quinoline group is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, —S—C ₁ -C ₆ alkyl, —CN, —OH, —NO ₂ or —.
It is selected from CF _3; R ₃ is hydrogen, alkyl of 1 to 6 carbon atoms, a group selected from alkoxy or halogen having 1 to 4 carbon atoms; R ₄ is hydrogen, 1 to 6 carbon atoms X represents a group selected from alkyl or R ₅ ; R ₅ is CH ₂ Ph, and the phenyl ring may be optionally substituted with a group selected from OMe, halogen or CF ₃ ; X Is selected from groups represented by N, CR ₄ , CHR ₄ and CHCH; A is selected from groups represented by N, NH, CH and CH ₂ ; B is ＝ O, ＳS, H is selected from the group represented by H _2; or, A and B are bonded together, indole, benzimidazole,
May form an indone or indoline moiety] or a pharmaceutically acceptable salt thereof.

Here, the kind of substitution represented by B in the generic group is such that A is N, NH, CH
Or it is understood to be regulated by whether they are CH _2.

The term “aryl” as used in the definition of R ₁ and R ₂ denotes a phenyl or pyridine group, optionally halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, —S—C _{6 1} -C ₆ alkyl, -CN, -OH, optionally substituted with 1-3 substituents selected from -NO ₂ or -CF _3. The most preferred aryl group is phenyl, which may be optionally substituted as described above. The most preferred arylalkyl group in the above definition is benzyl, and the preferred aralkyloxy group is benzyloxy.

The pharmaceutically acceptable salt is a compound represented by the above general formula and a pharmaceutically acceptable inorganic acid (eg, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid,
Fumaric acid, acetic acid, lactic acid or methanesulfonic acid).

The compound of the present invention may be produced, for example, using conventional methods utilizing the cleavage shown in the following schemes A and B.

[0012]

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In Scheme A, phenol 1 is reacted with an epoxide of Formula 2 to give the required product. The starting phenol is commercially available or
Alternatively, it can be easily obtained by a reaction carried out in the field of organic synthesis. Epoxide 2 is available, for example, from the reaction of an amine of formula 4 with an optically active or racemic epichlorohydrin or glycidyl tosylate.

In Scheme B, epoxide 3 can be obtained from the reaction of a phenol of Formula 1 with an optically active or racemic epichlorohydrin or glycidyl tosylate. Reaction of this compound with an amine of formula 4 gives the required product. The product can then be used to form pharmaceutically acceptable addition salts.

The compounds of the present invention bind with very high affinity to the 5-HT _1A receptor and the dopamine D ₂ receptor, so that they are effective in treating Alzheimer's disease, Parkinson's disease, obesity and migraine. In addition to treatment, central nervous system disorders (e.g., schizophrenia,
It is useful in treating depression, anxiety (including generalized anxiety), sleep disorders, sexual dysfunction, addiction to alcohol and cocaine, and related problems). The compounds of the present invention can also be used in therapies that increase cognitive enhancement. The present invention relates to a method for treating each of these diseases in a mammal, as well as a method for increasing cognition enhancement, and an effective amount of one or more compounds of the invention or a medicament thereof in a mammal in need thereof. And administering a pharmaceutically acceptable salt.

It is understood that the therapeutically effective dose to be used in the treatment of a particular psychiatric disorder must be subjectively determined by the attending physician. Relevant variables include the state of a particular mental illness or anxiety, as well as the physique, age and response pattern of the patient.
The novel methods of the present invention for treating conditions associated with or affected by serotonin reuptake are provided in warm-blooded animals, including humans, in an effective amount of at least one compound of the present invention or a non-toxic pharmaceutically active agent. Administering an acceptable addition salt. These compounds may be administered orally, rectally, parenterally, or topically on the skin and mucous membranes. The usual daily dose depends on the particular compound, the method of treatment and the condition being treated. Effective doses that can be used for oral administration are 0.01-100.
0 mg / kg, preferably 0.5-500 mg / kg, and the effective amount that can be used for parenteral administration is 0.1-100 mg / kg, preferably 0.5-50 mg / kg.

The present invention also includes a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

Applicable solid carriers or excipients include flavoring agents, lubricants, solubilizers, suspending agents, fillers, flow agents, compression aids, binders, and tablet disintegrants. One or more substances or encapsulating materials that can act can be mentioned. In powders, the carrier is a finely divided solid, which is in turn mixed with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include
For example, calcium phosphate, magnesium stearate, talc, sugar, lactose,
Dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, 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 the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. Liquid carriers are solubilizers, emulsifiers, buffers, preservatives, sweeteners,
Other suitable pharmaceutical additives such as flavoring agents, suspending agents, thickening agents, coloring agents, viscosity modifiers, stabilizers or penetrants can be included. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly an additive as described above, for example, containing a cellulose derivative, preferably sodium carboxymethylcellulose solution.
), Alcohols (including monohydric and polyhydric alcohols such as glycols) and derivatives thereof, and oils such as fractionated coconut and peanut oils. 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 that 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 can be in either liquid or solid composition form.

[0021] Preferably, the pharmaceutical composition is in unit dosage form, for example, a tablet or capsule. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active component, and the unit dosage form is a packaged composition, e.g.
It can be an ampoule, a filled syringe or a sachet containing liquid. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of such compositions in packaged form.

The affinity of the drug for the dopamine receptor is determined by the ability of the claimed compound to displace [ ³ H] -spiperone binding in CHO cells stably transfected with the human dopamine D ₂ receptor. Established by testing ability. Human
CHO cells expressing dopamine D ₂ receptors expanded in serum-free medium (3-4 days
) To obtain about 7.5 × 10 ⁵ cells / mL. Centrifuge the cells (9
00 × g for 10 minutes), resuspended in half of 1 × Dulbecco's PBS solution at pH 7.4, and after recentrifugation, the cell pellet was reconstituted with 1.5 mM CaCl _2.
5.0 mM EDTA, 5.0 mM KCl, 120 mM NaCl, 1.0 mM
50 mM Tris-HCl containing PMSF and 1.0 mg% leupeptin (
pH 7.4). The cells were homogenized, centrifuged at 40,000 xg for 30 minutes, resuspended in fresh buffer (10 mL), and the process was repeated twice. The final pellet was suspended in a sufficient volume of 50.0 mM Tris.HCl to obtain a protein concentration of 125.0 μg / mL of the membrane suspension. The binding assay was performed in a 96-well
Performed in microtiter plates. 100 μL of buffer is added to the wells and 80 μL of incubation buffer is placed in wells containing the displacer or test compound for non-specific binding (NSB) evaluation. [ ³ H] -Spiperone (S.
A. 89-100 Ci / mmol) as ligand and 0.5 in 20 μL volume.
After nM has been added to all wells, the replacement substance D-butaclamol (1 μM in 20 μL) for non-specific binding measurements is added. The reaction was started by adding 80 μL of tissue membrane and after 120 minutes at room temperature, Brandel Harvester (Brandel Harvester) was used.
l ^R Harvester) using, wells are collected in advance 0.1% polyethylene fiberglass on filters immersed in Rui Min. After three washes with cold 50 mM Tris-HCl, filter mats were oven dried and scintillation counting on a Wallac 1205 BetaPlate counter.
Seal into envelope with melted multitex. Analyze the data and calculate the Ki value for the active compound. Using this assay, a series of standard D ₂ receptor ligand was determined Ki below.

Compound D ₂ -linked Ki (nM) Spiperone 0.08 Clozapine 28.6 Haloperidol 0.57 7-OHDPAT 96 Sulpiride 49.4

The results for a number of examples of compounds of formula 1 in this standard experimental test are shown below.

Compound D ₂ Bond Ki (nM) Example 2 33.5 Example 5 31.9 Example 6 10.4

Claims wherein the high affinity for the serotonin 5-HT _1A receptor displaces [ ³ H] 8-OH-DPAT binding in CHO cells stably transfected with the human 5-HT _1A receptor. Was established by testing the ability of the compounds described in. Stably transfected CHO cells are grown in DMEM containing 10% heat-inactivated FBS and non-essential amino acids. The cells are scraped off the plate, transferred to a centrifuge tube and centrifuged (2000) in buffer (50 mM Tris, pH 7.5).
(10 min, 4 ° C.). The resulting pellet is aliquoted and stored at -80 ° C. On the day of the assay, the cells are thawed on ice and resuspended in buffer. The binding assay is performed in a total volume of 250 μL 96-well microtiter plate. Non-specific binding is measured in the presence of 10 mM 5-HT. Final ligand concentration is 1.5 nM. After incubating at room temperature for 30 minutes, ice-cold buffer was added, and G was pre-soaked in 0.5% PEI for 30 minutes.
The reaction is terminated by rapid filtration through an F / B filter. Compounds are first tested in a single-point assay to determine percent inhibition at 1, 0.1 and 0.01 mM and to determine Ki values for active compounds.

Compound 5-HT _1A binding Ki (nM) Example 1 6.0 Example 2 7.6 Example 3 1.8 Example 4 8.8 Example 5 12.1 Example 6 10.4 Example Example 7 7.2 Example 8 4.5

The following non-limiting specific examples are included to illustrate synthetic methods that can be used to prepare compounds of formula 1. In these examples, all chemicals and intermediates are commercially available or can be prepared by standard methods found in the literature or are known to those skilled in the art of organic synthesis. It is.

[0029] Example 1 1- (1H-indol-4-yloxy) -3- [4- (1H- indol-4-yl) - peak Perazine-1-yl] - propan-2-ol 1- (indole A solution of (-4-oxy) -2,3-epoxypropane (0.38 g, 2.0 mmol) in methanol (20 mL) was treated with 1- (indol-4-yl) -piperazine in methanol (75 mL) under a nitrogen atmosphere. (0.4 g, 2.0 mmol) was added dropwise to the stirred solution. The mixture was heated at reflux for 2 hours, concentrated in vacuo, and the product was purified by column chromatography on silica gel (CH ₂ Cl ₂ : MeOH = 95: 5) to give an oil (0.7 g, yield 90%). Treatment with a 0.25 M solution of fumaric acid in ethanol provided the required product. This was recrystallized from ethanol to give the title compound as a white solid. 147-150 ° C. Elemental analysis (as _{C 23 H 26 N 4 O 2} · 1.0C 4 H 4 O 4): Calculated: C, 64.02; H, 5.97 ; N, 11.06 Found: C, H, 6.36; N, 11.81.

Example 2 1- (4-Chloro-phenoxy) -3- [4- (1H-indol-4-yl) -piperazin- 1-yl] -propan-2-ol 4-chlorophenyl-2,3 A solution of -epoxypropyl ether (0.55 g, 3.0 mmol) and 1- (indol-4-yl) -piperazine (0.6 g, 3.0 mmol) in methanol (75 mL) was refluxed under a nitrogen atmosphere for 1 hour. did. The mixture is concentrated in vacuo and the product is chromatographed on silica gel (EtOAc: hexane =
90:10) to give a white solid (1.25 g, 100%). Treatment with a 0.25 M solution of fumaric acid in ethanol provided the required product. This was recrystallized from ethanol to give the title compound as a white solid. Melting point 224-225 [deg.] C. Elemental analysis (as _{C 21 H 24 ClN 3 O 2} · 0.5C 4 H 4 O 4): Calculated: C, 62.23; H, 5.9 ; N, 9.47 Found: C, 61.98; H, 5.79; N, 9.21.

Example 3 1- [4- (1H-Indol-4-yl) -piperazin-1-yl] -3- (4-methoxy-
Phenoxy) -propan-2-ol 4-methoxyphenyl-2,3-epoxypropyl ether (0.54 g, 3.0 mmol) and 1- (indol-4-yl) -piperazine (0.6 g, 3.0 (Mmol)
Was refluxed under a nitrogen atmosphere for 1 hour. The mixture is concentrated in vacuo and the product is chromatographed on silica gel (CH ₂ Cl ₂ : MeOH).
= 90:10) to give a white solid (1.1 g, 96%). Treatment with a 0.25 M solution of fumaric acid in ethanol provided the required product. This was recrystallized from ethanol to give the title compound as a white solid. 226-227 ° C. Elemental analysis (as _{C 22 H 27 N 3 O 3} · 0.5C 4 H 4 O 4): Calculated: C, 65.59; H, 6.65 ; N, 9.56 Found: C, H, 6.48; N, 9.36.

Example 4 1- [4- (1H-Indol-4-yl) -piperazin-1-yl] -3- (4-nitro-phenyl
Enoxy) -propan-2-ol 1,2-epoxy-3- (4-nitrophenoxy) -propane (0.59 g, 3.0 mmol) and 1- (indol-4-yl) -piperazine (0.6 g) (3.0 mmol) in methanol (65 mL) was refluxed for 1 hour under a nitrogen atmosphere. The mixture was concentrated in vacuo to give the product as a yellow solid (1.1 g, 93%). Treatment with a 4M solution of HCl in ether afforded the required product. This was recrystallized from ethanol to give the title compound as a light yellow solid. Melting point 248 [deg.] C. Elemental analysis (as _{C 21 H 24 N 4 O 4} · 1.0HCl): Calculated: C, 58.26; H, 5.82 ; N, 12.94 Found: C, 57.92; H , 5.76; N, 12.66.

Example 5 1- (2-Chloro-phenoxy) -3- [4- (1H-indol-4-yl) -piperazin- 1-yl] -propan-2-ol 1- (2-chlorophenoxy ) -2,3-Epoxypropane (0.55 g, 3.0 mmol) and 1- (indol-4-yl) -piperazine (0.6 g, 3.0 mmol) in methanol (75 mL) were added under a nitrogen atmosphere. For 1 hour. The mixture is concentrated in vacuo and the product is chromatographed on silica gel (CH ₂ Cl ₂ : MeOH = 9).
0:10) to give a white solid (1.09 g, 94%). 0 of fumaric acid
Treatment with a .25M ethanol solution provided the required product. This was recrystallized from ethanol to give the title compound as a white solid. 207 ° C. Elemental analysis (as _{C 21 H 24 ClN 3 O 2} · 0.5C 4 H 4 O 4): Calculated: C, 62.23; H, 5.9 ; N, 9.47 Found: C, 62.13; H, 5.72; N, 9.34.

Example 6 1- (4-Fluoro-phenoxy) -3- [4- (1H-indol-4-yl) -piperazi
1-yl] -propan-2-ol 1- (4-fluorophenoxy) -2,3-epoxypropane (0.50 g, 3.0 mmol) and 1- (indol-4-yl) -piperazine ( A solution of 0.6 g (3.0 mmol) in methanol (50 mL) was refluxed under a nitrogen atmosphere for 1 hour. The mixture was concentrated in vacuo and the product was purified by silica gel chromatography (EtOAc),
A white solid (1.1 g, 99%) was obtained. Treatment with a 0.25 M solution of fumaric acid in ethanol provided the required salt. This was recrystallized from ethanol to give the title compound as a white solid. 234-235 ° C. Elemental analysis (as _{C 21 H 24 FN 3 O 2} · 0.5C 4 H 4 O 4): Calculated: C, 64.62; H, 6.13 ; N, 9.83 Found: C, H, 6.01; N, 9.67.

Example 7 4- {2-hydroxy-3- [4- (1H-indol-4-yl) -piperazin-1-yl] -propoxy} -1H-indole-2-carboxylic acid amide 1- ( 2-carboxamidoindole-4-oxy) -2,3-epoxypropane (0
.83 g, 1.5 mmol) and 1- (indol-4-yl) -piperazine (0.6 g)
(3.0 mmol) in methanol (50 mL) was refluxed for 0.5 h under a nitrogen atmosphere. The mixture is concentrated in vacuo and the product is chromatographed on silica gel (
Purification with CH ₂ Cl ₂ : MeOH = 90: 10) gave a white solid (1.24 g, 9).
7%). Treatment with a 1.0 M solution of HCl in ether afforded the required product.
This was recrystallized from ethanol to give the title compound as a white solid. 258-259 ° C. Elemental analysis (as _{C 24 H 27 N 5 O 3} · 1.0HCl): Calculated: C, 60.5; H, 6.08 ; N, 14.7 Found: C, 60.31; H , 5.89; N, 14.6.

Example 8 1- (biphenyl-2-yloxy) -3- [4- (1H-indol-4-yl) -pipera
Zin-1-yl] -propan-2-ol 2-biphenylglycidyl ether (0.68 g, 1.5 mmol) and 1- (indol-4-yl) -piperazine (0.6 g, 3.0 mmol) Methanol solution (5
(0 mL) was refluxed under a nitrogen atmosphere for 15 hours. The mixture is concentrated in vacuo and the product is purified by silica gel chromatography (EtOAc) to give a white solid (
(1.23 g, 96%). Treated with a 0.25 M solution of fumaric acid in ethanol,
The required salt was obtained. This was recrystallized from ethanol to give the title compound as a white solid. Melting point 214-215 [deg.] C. Elemental analysis (as _{C 27 H 29 N 3 O 2} · 1.0C 4 H 4 O 4): Calculated: C, 68.49; H, 6.12 ; N, 7.73 Found: C, H, 6.12; N, 7.88.

Example 9 1- (1H-Indol-4-yloxy) -3- [4- (1H-benzimidazol-4- yl) -piperazin-1-yl] -propan-2-ol The title compound is Prepared from 1- (indole-4-oxy) -2,3-epoxypropane (2.0 mmol) and 1- (1H-benzimidazol-4-yl) -piperazine (2 mmol) according to the method described above.

[0038] Example 10 1-(1H-indol-4-yloxy) -3- [4- (1H-2,3- dihydroindolo Lumpur 4-yl) - piperazin-1-yl] - propan-2 All title compounds were prepared using the procedure outlined in the previous example, using 1- (indole-4-oxy) -2,3-epoxypropane (2.0 mmol) and 1- (1H-2,3-dihydro Prepared from indole-4-yl) -piperazine (2 mmol).

Example 11 1- (1H-Indol-4-yloxy) -3- [4- (1H-2-oxindol-4 -yl) -piperazin-1-yl] -propan-2-ol Title Compound Was prepared using the method outlined in the previous example, using 1- (indole-4-oxy) -2,3-epoxypropane (2.0 mmol) and 1- (1H-2-oxindol-4-yl). Prepared from) -piperazine (2 mmol).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/18 A61P 25/18 25/22 25/22 25/24 25/24 25/28 25/28 43 / 00 111 43/00 111 C07D 209/34 C07D 209/34 209/42 209/42 403/12 403/12 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM) , AE, AL, AM, AT, AU, A , BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, 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, ZA, ZW (72) Inventor Jan Hee Kang United States of America 08691 Andover Place, Robinsville, NJ 324 F term (reference) 4C063 AA01 BB07 CC26 DD06 EE01 4C086 AA01 AA02 AA03 BC13 BC50 GA07 MA01 MA04 NA14 ZA02 ZA12 ZA16 ZA18 ZC42 4C204 BB01 CB03 DB01 DB29 DB03 GB24 GB25 GB32 Pharmaceutical compositions and methods.

Claims (14)

[Claims] 1. The formula: embedded image [Wherein, R ₁ and R ₂ each independently represent H, OH, F, Cl, Br, I, carbon number 1 to
6 alkyl or alkenyl, C 1-6 alkoxy, aryl, arylalkyl, aralkyloxy, OR ₅ , nitro, amino or CF ₃ , and R ₁ and R ₂ when taken together are 1 Form a fused ring at the 2,2- or 2,3-position to give a fused phenyl or benzodioxane group, or a 4- or 7-substituted indole group, or a 4- or 5- or 8-substituted quinoline group , The substituent on the indole or quinoline group is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, —S—C ₁ -C ₆ alkyl, —CN, —OH, —NO ₂ or —.
Is selected from CF _3; or, R ₂ and R ₂ taken together, form a ring fused with 1,2- or 2,3-position, fused phenyl group or benzodioxane group, or 4, - or give 7-substituted indole group, or 4- or 5- or 8-substituted quinoline group; R ₃ is selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy or halogen having 1 to 4 carbon atoms represents a group; R ₄ is hydrogen, a group selected from alkyl or R ₅ having 1 to 6 carbon atoms; the R _5, a CH ₂ Ph, wherein the phenyl ring is optionally, OMe, halogen or a group selected from CF ₃ may be substituted; X is selected from the group shown with N, CR _4, CHR ₄ and CHCH; A is indicated N, NH, with CH and CH ₂ B is selected from the group: , = S, H and H ₂ is selected from the group represented by; or, A and B are bonded together, indole, benzimidazole,
Or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which is 1- (1H-indol-4-yloxy) -3- [4- (1H-indol-4-yl) -piperazin-1-yl] -propan-2-ol. Or a pharmaceutically acceptable salt thereof. 3. 3- (4-Chloro-phenoxy) -3- [4- (1H-indole-4-
2. The compound according to claim 1, which is yl) -piperazin-1-yl] -propan-2-ol, or a pharmaceutically acceptable salt thereof. 4. 1- [4- (1H-indol-3-yl) -piperazin-1-yl]-
The compound according to claim 1, which is 3- (4-methoxy-phenoxy) -propan-2-ol, or a pharmaceutically acceptable salt thereof. 5. 1- [4- (1H-indol-4-yl) -piperazin-1-yl]-
The compound according to claim 1, which is 3- (4-nitro-phenoxy) -propan-2-ol, or a pharmaceutically acceptable salt thereof. 6. A method for preparing 1- (2-chloro-phenoxy) -3- [4- (1H-indole-4-).
2. The compound according to claim 1, which is yl) -piperazin-1-yl] -propan-2-ol, or a pharmaceutically acceptable salt thereof. 7. 1- (4-Fluoro-phenoxy) -3- [4- (1H-indole-4
-Yl) -piperazin-1-yl] -propan-2-ol or a pharmaceutically acceptable salt thereof. 8. The compound according to claim 1, which is 4- {2-hydroxy-3- [4- (1H-indol-4-yl) -piperazin-1-yl] -propoxy} -1H-indole-2-carboxylic acid amide. 2. The compound according to 1 or a pharmaceutically acceptable salt thereof. 9. A mixture of 1- (biphenyl-2-yloxy) -3- [4- (1H-indole-
4. The compound according to claim 1, which is 4-yl) -piperazin-1-yl] -propan-2-ol, or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 1, which is 1- (1H-indol-4-yloxy) -3- [4- (1H-benzimidazol-4-yl) -piperazin-1-yl] -propan-2-ol. Or a pharmaceutically acceptable salt thereof. 11. 11- (1H-indol-4-yloxy) -3- [4- (1H-2,
The compound according to claim 1, which is 3-dihydroindol-4-yl) -piperazin-1-yl] -propan-2-ol, or a pharmaceutically acceptable salt thereof. (12) 1- (1H-indol-4-yloxy) -3- [4- (1H-2-
The compound according to claim 1, which is oxindol-4-yl) -piperazin-1-yl] -propan-2-ol, or a pharmaceutically acceptable salt thereof. 13. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 14. A method for treating schizophrenia in a mammal, comprising administering to a mammal in need thereof an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof. How to be.