EP1076658A1

EP1076658A1 - Serotonergic agents

Info

Publication number: EP1076658A1
Application number: EP99920078A
Authority: EP
Inventors: Michael Gerard Kelly; Young Hee Kang
Original assignee: American Home Products Corp
Current assignee: Wyeth LLC
Priority date: 1998-04-29
Filing date: 1999-04-28
Publication date: 2001-02-21
Also published as: AU3765899A; CA2330577A1; WO1999055697A1; JP2002513018A; CN1307576A; AR015035A1

Abstract

The present invention provides compounds represented by general formula (1), wherein: R1 is selected from H, OH,OR3, F, C1, Br, or I; R2 in each occurrence is H or both together are =O; R3 and R4 are independently selected from H, C1 to C6 alkyl or (CH2)nAr, the alkyl and Ar groups being optionally substituted by from 1 to 3 groups selected from NO2, F, C1, Br, I, -OH, -OR3, C1-C6 alkyl, C1-C6 alkoxy, -CF3, -CN, -S-C1-C6 alkyl, or -NH2; n is selected from 0, 1 or 2; X is CH or CH2; R2 is H or taken together are =O; Ar is aryl or heteroaryl, both optionally substituted; or a pharmaceutically acceptable salt thereof, as well as methods and pharmaceutical compositions utilizing these compounds for the inhibition of serotonin uptake and the treatment of CNS disorders, including depression.

Description

SEROTONERGIC AGENTS

This application claims the benefit of U.S. Provisional Application No. 60/100,434, which was converted from U.S. Patent Application No. 09/069,041, filed April 29, 1998, pursuant to a petition filed under 37 C.F.R. 1.53(c)(2)(i).

This invention relates to novel indolyl derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in therapy. The novel compounds are useful for the treatment of central nervous system disorders, particularly depression, by virtue of their ability to inhibit the uptake of serotonin.

Background to the Invention

Depression is a psychiatric condition thought to be associated with decreased serotonin release. Most antidepressant agents potentiate the effects of serotonin by blocking the termination of its activity through re-uptake into nerve terminals.

U.S. Pat. No. 5,565,447 (Forner et al.) teaches indole derivatives useful in treating migraine headaches and other conditions in which the indole core is substituted in the 3-position by substituents of the formula -CH_J-CH_J-NR'R², wherein R¹ and R² are selected from hydrogen or an alkyl group, and substituted in the 5-position by substituents of the formula -CH₂-SO₂-Z, wherein Z represents a ring selected from:

(CH₂)_n N- o N- ( N- R⁶OOC-N N-

wherein n is 4, 5 or 6; R³ is H or alkyl; R⁴ is alkyl, methoxy benzyl or R⁵NHCO; and R⁵ and R⁶ are alkyl groups.

U.S. Pat. No. 5,607,960 (Wythes) teaches additional 3,5-disubstituted indole compounds which act as selective agonists on 5-hydroxytryptamine receptors and are useful in treating migraines and associated maladies such as cluster headaches, chronic paroxysmal hemicrania and headache associated with vascular disorders. - 2

U.S. Pat. No. 5,607,961 (Cipollina et al.) teach 3-amino-cycloalkanyl and cycloakenyl derivatives of 5-cyano-substituted indoles which are useful as antidepressant agents.

U.S. Pat. No. . 5,639,752 (Macor) teach further 3,5-disubstituted indole compounds useful in treating migraines and related disorders wherein the indole 3- position is substituted by groups of the formulae:

R₃

R₂

B

^R4\_^ Λ /

R₃— B or

FV ^

F I R₄' r R₅ Re and substituted in the 5-position by groups selected from the formulae:

. ₇

TM

,NR₇R₈- ^A r

<13 or

wherein X is O, NH, or S; A, B, D, E and F are C, N, O or S.

U.S. Pat. No. 5,639,772 (Hammarberg et al.) discloses 3-amino-5-aryl- and 5- heteroarylchromans which are useful in the treatment of 5-hydroxytryptamine-mediated disorders of the central nervous system.

Summary of the Present Invention

Compounds of the present invention are represented by the general formula (1) 3 -

Ar

(1) wherein:

R, is selected from H, -OH, -OR₃, F, CI, Br, or I;

R, in each occurrence is H or both together are =O;

R₃ and R₄ are independently selected from H, C, to C₆ alkyl or (CH₂)nAr, the alkyl and Ar groups being optionally substituted by from 1 to 3 groups selected from NO₂, F, CI, Br, I, -OH, -OR₃, C,-C₆ alkyl, C,-C₆ alkoxy, -CF₃, -CN, -S-C,-C₆ alkyl, or -NH₂; n is an integer selected from 0, 1 or 2;

X is CH or CH₂;

Ar is monocyclic or bicyclic aryl or heteroaryl moieties, each optionally substituted by from one to three groups selected from -NO₂, F, CI, Br, I, -OH, -OR₃, C,-C₆ alkyl, C,-C₆ alkoxy, -CF₃, -CN, -S-C,-C₆ alkyl, or -NH₂; or a pharmaceutically acceptable salt thereof.

The preferred aryl and heteroaryl groups referred to herein as Ar include phenyl, benzyl, pyridinyl, pyrimindinyl, pyrazinyl, furyl, thienyl, pyrrolyl, indolyl, napthyl, benzodioxanyl, or quinolyl. Among the more preferred Ar groups are phenyl, pyridinyl, furyl and napthyl moieties, optionally substituted.

The pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable inorganic acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, furmaric, acetic, lactic or methanesulfonic acid. - 4

Detailed Description of the Invention

Compounds of the present invention may be prepared using conventional methods. For example, the appropriately substituted indole (A) can be coupled with a chloromethylamide (B) using a base such as diisopropylethylamine. The amide so produced can be used to form a pharmaceutically acceptable salt, or optionally may be reduced to the a ine using a hydride reducing agent such as lithium aluminium hydride.

H Ar— N

R₂

N Ar

Or B (CH₂)n

Base

R₃ \ R₃

The preparation of the appropiately substituted 3-(4-piperidinyl)indoles and 3-

(4-tetrahydro pyridinyl) indoles can be acheived by known and convential methods.

For example, the reaction of an optionally substituted indole (D) with 4-piperidone (E) affords the 3-(4-tetrahydropyridinyl)indole (F). This can be reduced using standard catalytic hydrogenation methodology to afford a 3-(4-piperidinyl)indole (G). Such methodology is described in C. Gueremy et al., J. Med. Chem., 1980, 23, 1306-1310;

J-L. MaUeron et al., J. Med. Chem., 1993, 36, 1194-1202; J. Bergman, J.

Heterocyclic. Chem., 1970, 1071-1076 and J. Guillaume et al, Eur. J. Med. Chem.,

1987, 22(1), 33-34. °0

+

Ri

The preparation of the appropiately substituted 3-(4-piperidinylmethyl)indoles (H) and 3-(4-tetrahydropyridinylmethyl)indoles (I) can also be acheived by known and convential methods. Such methodology is described in C. Gueremy et al., J. Med. Chem., 1980, 23, 1306-1310; J-L. Malleron et al., J. Med. Chem., 1993, 36, 1194- 1202 and J. Bergman, J. Heterocyclic. Chem., 1970, 1071-1076

Ri

H I

Compounds of the present invention inhibit with very high affinity the binding of paroxetine to the serotonin transporter and, consequently, they are useful as antidepressant and anxiolytic agents and cognition enhancement agents for the treatment of central nervous system disorders such as depression, anxiety, sleep disorders, sexual dysfunction, alcohol and ***e addiction, and related problems, as well as in being useful in cognition enhancement or in inhibition of depletion thereof. In addition, compounds of the present invention may be used in conjunction with an agonist or antagonist of the serotonin- 1 receptor (5-HT1) to aid or enhance the compounds biological properties. Such compositions are useful for the above mentioned 5-HT1- related disorders in addition to the treatment of Alzheimer's disease, Parkinson's disease, schizophrenia, obesity and migraine. The present invention includes methods for treating each of these maladies, the methods comprising administering to a mammal in need thereof a pharmaceutically effective amount of one or more compounds herein, or a pharmaceutically acceptable salt thereof.

It is understood that the therapeutically effective dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician. Variables involved include the specific psychosis or state of anxiety and the size, age and response pattern of the patient. The novel method of the invention for treating conditions related to or are affected by the reuptake of serotonin comprise administering to warm-blooded animals, including humans, an effective amount of at least one compound of this invention or a non- toxic, pharmaceutically acceptable addition salt thereof. The compounds may be administered orally, rectally, parenterally, or topically to the skin and mucosa. The usual daily dose is depending on the specific compound, method of treatment and condition treated. An effective dose of 0.01 - lOOOmg/Kg may be used for oral application, preferably 0.5 - 500 mg/Kg, and an effective amount of 0.1 - 100 mg/Kg may be used for parenteral application, preferably 0.5 - 50 mg/Kg.

The present invention also includes pharmaceutical compositions containing a compound of this invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

Applicable solid carriers or excipients 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 7 -

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 affinity of drugs for the serotonin transporter was determined by assessing the ability of agents to displace specifically bound 3H-paroxetine binding from rat cortical membranes. This procedure is a modification of that used by Cheetham et al., 1993 (Neuropharmacol. 32:737-743, 1993). Nonspecific binding was determined using fluoxetine. Using this assay, the following Ki's were determined for a series of standard serotonin uptake inhibitors. ³H-Paroxetine Binding to Assess Affinity of Drugs for the Serotonin Transporter:

A protocol similar to that used by Cheetham et al. (Neuropharmacol. 32:737, 1993) was used to determine the affinity of compounds for the serotonin transporter. Briefly, frontal cortical membranes prepared from male S.D. rats were incubated with ³H-paroxetine (0.1 nM) for 60 min at 25°C. All tubes also contained either vehicle, test compound (one to eight concentrations), or a saturating concentration of fluoxetine (10 μM) to define specific binding. AH reactions are terminated by the addition of ice cold Tris buffer followed by rapid filtration using a Tom Tech filtration device to separate bound from free ³H-paroxetine. Bound radioactivity was quantitated using a Wallac 1205 Beta Plate® counter. Nonlinear regression analysis was used to determine IC₅₀ values which were converted to Ki values using the method of Cheng and Prusoff (Biochem. Pharmacol. 22: 3099, 1973); Ki = IC50/((Radioligand conc.)/(l + KD)).

Compound Inhibition of r3H1-Paroxetine binding

Ki (nM) Clomipramine 0.18

Fluoxetine 4.42 Imipramine 17.6

Zimelidine 76.7

The results for a number of examples of compounds of formula 1 in this standard experimental test procedure were as follows:

Compound Inhibition of r3H1-Paroxetine binding

Ki (nM)

Example 1 0.09

Example 2 2.72

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

2-r4-(5-Fluoro-lH-indoI-3-ylmethyl)-piDeridin-l-yl1-

N-pyridin-2-yl-acetamide

Pulverized potassium carbonate was added to a mixture of 4-(5-fluoro-lH- indol-3-ylmethyl)piperidine (0.58 g, 2.5 mmole) and 2-(2-chloroacetamido)pyridine (0.43 g, 2.5 mmole) in 50 ml of DMF. The resulting solution was heated at 80 °C for 15 hours and the cooled mixture was partitioned between methylene chloride and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The oily residue was chromatographed over silica gel using ethyl acetate as eluant. This provided the required compound as a white solid (0.84 g, 92 %, 2.3 mmole). The free base was dissolved in 20 ml of ethanol and treated with 10 ml of 0.25 M ethanolic fumaric acid to afford a white crystalline solid which was recrystallized further from ethanol to give the title compound as its fumaric acid salt. m.p. 194 °C.

Elemental Analysis for: C21H23FN4O . 0.5 C4H4O4 . 0.67 C2H6O Calculated: C, 64.20; H, 6.42; N, 12.30 Found: C, 64.24; H, 6.38; N, 12.02

Example 2

{2-r4-(5-Fluoro-lH-indol-3-ylmethyl)-DiDeridin-l-yll- ethyll-pyridin-2-yl-amine

Lithium aluminum hydride (0.21 g, 5.5 mmole) in dry THF (50 ml) was placed in a three- necked flask under a nitrogen atmosphere. 2-[4-(5-Fluoro-lH-indol-3- ylmethyl)-piperidin-l-yl]-N-pyridin-2-yl-acetamide ( 0.4 g, 1.1 mmole) was dissolved in 25 ml of dry THF, and the resulting solution was slowly introduced dropwise to the above stirred suspension at 0 °C. The mixture was then heated to a gentle reflux and stirred for 15 hours. The reaction mixture was cooled to room temperature and the excess hydride was destroyed with the addition of 5 ml of 1 : 1 mixture of THF and water at 0 °C. Stirring was continued as 15 ml of 2.5 N NaOH solution was added to coagulate the precipitate of aluminum hydroxide. The mixture was filtered, washed with 25 % isopropanolic methylene chloride solution, and the solution dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was - 10 -

chromatographed on silica gel using ethyl acetate and 5 % methanolic ethyl acetate as eluents to give 0.26 g (67 %, 0.7 mmole) of the expected product as an oily liquid. The free base was dissolved in 10 ml of ethanol, treated with 1.4 ml of 1 M ethereal HC1

(1.4 mmol, 2 eq of free base ) to give a white solid, which was recrystallized further from ethanol to give the title compound. m.p. 223 - 224 °C.

Elemental Analysis for: C21H25FN4 . 2HC1 . 0.25H2O

Calculated: C, 58.67; H, 6.45; N,13.03

Found: C, 58.77; H, 6.39; N,12.60

Example 3 2-r4-(lH-Indol-3-yl⁾-piperidin-l-yI1-N-pyridin-2-yl-acetamide

A solution of 4-(lH-Indol-3-yl)-piperidine (1 g, 5.0 mmol), 2-(2- chloroacetamido)pyridine (0.93 g, 5.5 mmol) and diisopropylethylamine (0.64 g, 5 mmol) in dimethylformamide (6 ml) was stirred under an atmosphere of nitrogen at 70 °C for sixteen hours. The solution was cooled to room temperature, water (100 ml) added, and the product was extracted into ethyl acetate (4 x 60 ml). The combined organic solution was washed with water (50 ml) and dried over anhydrous sodium sufate. Filtration and concentration in vacuo gave 1.35 g of crude product. This was purified by chromatography on silica gel, using ethyl acetate as the eluant. The product so obtained was treated with one equivalent of 1N-HC1 to afford the title compound as a buff colored solid, m.p. 161 °C. Elemental Analysis for: C20H22N4O . HC1 . H2O Calculated: C, 61.77; H, 6.48; N,14.41 Found: C, 61.48; H, 6.06; N,14.29

Example 4 2-r4-(lH-Indol-3-yl⁾-3.6-dihvdro-2H-pyridin-l-vn-

N-pyridin-2-yl-acetamide

A solution of 4-(lH-Indol-3-yl)-3,6-dihydro-2H-pyridine (1.98 g, 10.0 mmol),

2-(2-chloroacetamido)pyridine (1.83 g, 11.0 mmol) and diisopropylethylamine (1.29 g, 10 mmol) in dimethylformamide (10 ml) was stirred under an atmosphere of nitrogen at 11

70 °C for sixteen hours. The solution was cooled to room temperature, water (100 ml) added, and the product was extracted into ethyl acetate (4 x 100 ml). The combined organic solution was washed with water (2 x 50 ml) and dried over anhydrous sodium sufate. Filtration and concentration in vacuo gave 3.2 g of crude product. This was purified by chromatography on silica gel, using ethyl acetate as the eluent. An ethanolic solution of the product so obtained was treated with 0.5 equivalents of fumaric acid to afford the salt of the title compound as a yellow colored solid. m.p. 174 °C.

Elemental Analysis for: C20H22N4O . 0.5 C4H4O4 Calculated: C, 67.68; H, 5.68; N,14.35 Found: C, 67.46; H, 5.63; N,14.68

Example 5 2-r4-(5-Fluoro-lH-indol-3-ylmethyl)-piDeridin-l -yl1- N-2.6-dimethylphenylacetamide

The title compound is produced by adding pulverized potassium carbonate to a mixture of 4-(5-fluoro-lH-indol-3-ylmethyl)piperidine (0.58 g, 2.5 mmole) and N- chloroacetyl-2,6-dimethylanaline (0.49 g, 2.5 mmole) in 50 ml of DMF. The resulting solution is then heated at 75 °C for 15 hours and the cooled mixture was partitioned between methylene chloride and water. The organic layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The oily residue is chromatographed over silica gel using ethyl acetate as eluant. This provides the required compound as a white solid (0.81 g, 86 %). The free base is then dissolved in 20 ml of ethanol and treated with 10 ml of 0.25 M ethanolic fumaric acid to afford a white crystalline solid which is recrystallized further from ethanol to give the title compound as its fumaric acid salt.

Example 6 2-r4-(2-Methyl-5-fluoro-lH-indol-3-ylmethyl)-piperidin-l-vn-

N-2-nitrophenylacetamide

The title compound is produced by adding pulverized potassium carbonate to a mixture of 4-(2-methyl-5-fluoro-lH-indol-3-ylmethyl)piperidine (0.59 g, 2.5 mmole) and α-chloro-2-nitroacetanilide (0.54 g, 2.5 mmole) in 50 ml of DMF. The resulting 12

solution is then heated at 80 °C for 16 hours and the cooled mixture is partitioned between methylene chloride and water. The organic layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The oily residue is chromatographed over silica gel using ethyl acetate as eluant. This provides the required compound as a light yellow solid (0.87 g, 88 %). The free base is then dissolved in 20 ml of ethanol and treated with 10 ml of 0.25 M ethanolic fumaric acid to afford a white crystalline solid which is recrystallized further from ethanol to give the title compound as its fumaric acid salt.

Example 7

I2-r4-(5-Methoxy-lH-indoI-3-ylmethyl)-piperidin-l-yll- ethyl)-(4-fluorophenyl)-amine

Lithium aluminum hydride (0.21 g, 5.5 mmole) in dry THF (50 ml) is placed in a three- necked flask under a nitrogen atmosphere. 2-[4-(5-Methoxy-lH-indol-3- ylmethyl)-piperidin-l-yl]-N-(4-fluorophenyl)-acetamide ( 0.5 g, 1.2 mmole) is dissolved in 25 ml of dry THF, and the resulting solution is slowly introduced dropwise to the above stirred suspension at 0 °C. The mixture is then heated to a gentle reflux and stirred for 15 hours. The reaction mixture is cooled to room temperature and the excess hydride is destroyed with the addition of 5 ml of 1:1 mixture of THF and water at 0 °C. Stirring is continued as 15 ml of 2.5 N NaOH solution is added to coagulate the precipitate of aluminum hydroxide. The mixture is filtered, washed with 25 % isopropanolic methylene chloride solution, and the solution dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product is chromatographed on silica gel using ethyl acetate and 5 % methanolic ethyl acetate as eluents to give 0.33 g (68 %, 0.86 mmole) of the expected product as an oily liquid. The free base is dissolved in 10 ml of ethanol, treated with 1.4 ml of 1 M ethereal HC1 (1.7 mmol) to give a white solid, which is recrystallized further from ethanol to afford the title compound. 13 -

Example 8

2-r4-(l-Methyl-5-methoxyindol-3-ylmethyl)-piperidin-l-yll-

N-2.6-dichlorophenylacetamide

The title compound is produced by adding pulverized potassium carbonate to a mixture of 4-(l-methyl-5-methoxyindol-3-ylmethyl)piperidine (0.61 g, 2.5 mmole) and 2-chloro-N-(2,6-dichlorophenyl)acetamide (0.59 g, 2.5 mmole) in 50 ml of DMF. The resulting solution is heated at 75 °C for 14 hours and the cooled mixture is partitioned between methylene chloride and water. The organic layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The oily residue is chromatographed over silica gel using ethyl acetate as eluant. This provides the required compound as a white solid (0.92 g, 82 %,). The free base is dissolved in 20 ml of ethanol and treated with 10 ml of 0.25 M ethanolic fumaric acid to afford a white crystalline solid which is recrystallized further from ethanol to give the title compound as its fumaric acid salt.

Claims

- 14 -What is Claimed:

1. A compound according the formula:

wherein

R, is selected from H, OH, OR₃, F, CI, Br, or I;

R_j in each occurrence is H or both together are =O; R₃ and R₄ are independently selected from H, C, to C₆ alkyl or (CH₂)nAr, the alkyl and Ar groups being optionally substituted by from 1 to 3 groups selected from NO₂, F, CI, Br, I, -OH, -OR₃, C,-C₆ alkyl, C,-C₆ alkoxy, -CF₃, -CN, -S-C_rC₆ alkyl, or -NH₂; n is selected from 0, 1 or 2; X is CH or CH₂;

R_j is H or taken together are =O;

Ar is selected from phenyl, benzyl, pyridinyl, pyrimindinyl, pyrazinyl, furyl, thienyl, pyrrolyl, indolyl, napthyl, benzodioxanyl, or quinolyl, each optionally substituted by from one to three groups selected from NO₂, F, CI, Br, I, -OH, -OR₃, C,-C₆ alkyl, C,-C₆ alkoxy, -CF₃, -CN, -S-C_rC₆ alkyl, or -NH₂; or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 which is 2-[4-(5-Fluoro-lH-indol-3-ylmethyl)- piperidin- 1 -yl]-N-pyridin-2-yl-acetamide or a pharmaceutically acceptable salt thereof. 15

3. A compound of claim 1 which is {2-[4-(5-Fluoro-lH-indol-3-ylmethyl)- piperidin-1-yl] -ethyl }-pyridin-2-yl-amine or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 which is 2-[4-(lH-Indol-3-yl)-piperidin-l-yl]- N-pyridin-2-yl-acetamide or a pharmaceutically acceptable salt thereof.

5. A compound of claim 1 which is 2-[4-(lH-Indol-3-yl)-3,6-dihydro-2H- pyridin-l-yl]-N-pyridin-2-yl-acetamide or a pharmaceutically acceptable salt thereof.

6. A compound of claim 1 which is 2-[4-(5-Fluoro-lH-indol-3-ylmethyl)- piperidin-l-yl]-N-(2,6-dimethylphenyl)acetamide or a pharmaceutically acceptable salt thereof.

7. A compound of claim 1 which is 2-[4-(2-Methyl-5-fluoro-lH-indol-3- ylmethyl)-piperidin-l-yl]-N-2-nitrophenylacetamide or a pharmaceutically acceptable salt thereof.

8. A compound of claim 1 which is {2-[4-(5-Methoxy-lH-indol-3- ylmethyl)-piperidin-l-yl]-ethyl}-(4-fluorophenyl)-amine or a pharmaceutically acceptable salt thereof.

9. A compound of claim 1 which is 2-[4-(l-Methyl-5-methoxyindol-3- ylmethyl)-piperidin-l-yl]-N-2,6-dichlorophenylacetamide or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound of Claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

11. A method for treating anxiety or depression in a mammal, the method comprising administering to the mammal in need thereof an amount effective to alleviate the anxiety or depression of a compound of Claim 1, or a pharmaceutically acceptable salt thereof. 16

12. A method for treating a cognition disorder in a mammal, the method comprising administering to the mammal in need thereof an amount effective to alleviate the cognition disorder of a compound of Claim 1 , or a pharmaceutically acceptable salt thereof.

13. The method of Claim 12 wherein the cognition disorder is Alzheimer's disease.

14. The method of Claim 12 wherein the cognition disorder is Parkinson's disease

15. The method of Claim 12 wherein the cognition disorder is schizophrenia.

16. A method for inducing cognition enhancement in a mammal, the method comprising administering to the mammal in need thereof an amount effective to alleviate the cognition disorder of a compound of Claim 1 , or a pharmaceutically acceptable salt thereof.