JP2002532473A - 1,4-piperazine derivatives having 5-HT1A receptor activity - Google Patents

Abstract

(57) [Summary] Formula (A): [Formula 1] Are useful for treating disorders of the central nervous system, such as anxiety, depression, depression, addiction to alcohol and drugs, sexual dysfunction, sleep disorders, cognitive impairment, Alzheimer's disease, Parkinson's disease, etc. .

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to a novel arylpiperazine derivative.

BACKGROUND OF THE INVENTION US Pat. No. 4,977,159 discloses 2-[(4-piperidyl) methyl] -1,2,3,4-tetrahydro-9H-pyrido [3,4-β] indole derivatives and Their application in treating depression, anxiety or hypertension is described.

DISCLOSURE OF THE INVENTION According to the present invention, there are provided novel arylpiperazine derivatives that are agonists and antagonists of the 5-HT1A receptor subtype. The compound of the present invention is 5-HT1
Due to their high avidity for A receptors, central nervous system (CNS) disorders such as depression, anxiety, depression, obsessive-compulsive disorder (OCD), sleep disorders, sexual dysfunction, addiction to alcohol and drugs, cognition It is useful for treating disorders, Alzheimer's disease, Parkinson's disease, obesity, migraine and the like.

The compound of the present invention has the general formula (A):

[0005]

Embedded image Wherein R ₁ is aryl or heteroaryl; A is NR ₂ or CH ₂ , B is NR ₂ or CH ₂ (where A is not the same as B); R ₂ is hydrogen, alkyl, cycloalkyl , Alkylcycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, aryl, aralkyl, heteroaryl, alkylheteroaryl or COR ₃ ; R ₃ is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; , An integer of 0 to 2] or a pharmaceutically acceptable salt thereof.

In some preferred embodiments of the present invention, R₁Is phenyl; 2-, 3-, or
4-pyridyl; 2-pyrimidyl; benzodioxan-5-yl; indol-4-yl
3-thienyl; 1- or 2-naphthyl. In a more preferred embodiment, R
₁Is phenyl or indol-4-yl. Some preferred of the present invention
In a specific example, R₂Is aralkyl, alkylheterocycloalkyl or COR ₃ It is.

As used herein, “alkyl” means a branched or straight chain having 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms. Specific examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl and the like. Lower alkyl means alkyl having 1 to 6 carbon atoms.

“Alkoxy” as used herein refers to an alkyl-O group. Here, the alkyl group is as described above. Specific examples of the alkoxy group include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy and the like.

“Aryl” as used herein means a monocyclic or bicyclic aromatic ring having 6 to 10 carbon atoms. Monocyclic rings are preferably 6-membered rings, and bicyclic rings preferably have an 8, 9 or 10-membered ring structure. Specific aryl groups include phenyl, naphthyl, biphenyl and the like. In some preferred embodiments,
Aryl is phenyl, 1-naphthyl or 2-naphthyl. In a more preferred embodiment, the aryl is phenyl. An aryl group may be substituted with one or more substituents. A substituted aryl group preferably has 1 to 3 substituents.

“Cycloalkyl” as used herein means a monocyclic alkyl group having 3 to 8 carbon atoms. In some preferred embodiments, the cycloalkyl is optionally substituted with 1-3 substituents.

As used herein, “heterocycloalkyl” refers to a 3- to 8-membered monocyclic alkyl group containing one or more, preferably one or two, heteroatoms selected from N and O. I do. Specific heterocycloalkyl groups include piperidinyl, piperazinyl, morpholino, and the like. In some preferred embodiments, the heterocycloalkyl group is optionally substituted with 1-3 substituents.

[0012] Halogen as used herein means fluorine, chlorine, iodine and bromine.

“Heteroaryl” means a 5-10 membered monocyclic or bicyclic aromatic ring having 1-3 heteroatoms selected from N, O and S. Monocyclic rings are
It is preferably 5- or 6-membered, and the bicyclic ring preferably has an 8-, 9- or 10-membered ring structure. Specific examples of the heteroaryl include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, benzopyranyl, benzodioxanyl and the like.
Preferred heteroaryl groups include thienyl, pyridyl, furyl, indolyl, benzodioxanyl and the like. More preferably, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 3-furyl
It is a heteroaryl group such as indolyl, indol-4-yl and benzodioxan-5-yl. Heteroaryl groups may be substituted with one or more substituents. A substituted heteroaryl group preferably has 1 to 3 substituents.

Suitable substituents include, unless otherwise specified, halogen, alkyl, hydroxy, alkoxy, amino, amide, nitro, alkylamino, alkylamide, perhaloalkyl, carboxyalkyl, carboxy, carbamide, dialkylamino, aryl, etc. Is mentioned.

The number of carbon atoms means the number of carbon atoms present in the carbon skeleton, and does not include carbon atoms present in substituents such as an alkyl group and an alkoxy group.

Where terms are used in combination, the definitions apply to each part of the combination unless otherwise noted. For example, alkylcycloalkyl is an alkyl-cycloalkyl group. Here, alkyl and cycloalkyl are as described above.

A pharmaceutically acceptable salt is a compound represented by the above general formula and a pharmaceutically acceptable acid,
For example, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, succinic acid,
It is an acid addition salt that can be formed from fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and the like.

The compounds of the present invention contain chiral centers and define various stereoisomers of these compounds, for example, racemic mixtures and individual optical isomers. The individual isomers
It can be produced directly, by an asymmetric synthesis method or a stereospecific synthesis method, or by a conventional method of separating an optical isomer from a racemic mixture.

The compounds of the present invention can be prepared by those skilled in the art of organic synthesis using conventional methods employing readily available reagents and raw materials.

For example, the condensation of an aryl-substituted piperazine with an appropriately protected derivative of nipecotic acid or isonicopetic acid gives the amides shown in Schemes A and B below. The reaction is performed in the presence of activating reagents such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (DAEC), 1-hydroxybenzotriazole hydrate (HOBT) and 4-methylmorpholine (NMM). It should be done in.

[0021]

Embedded image

[0022] Tert-butyl carbamate is an example of a suitable protecting group (P) and can be removed by the action of an acid. The desired unsubstituted product A can be obtained by deprotection to the amine and subsequent reduction of the amide with lithium aluminum hydride or borane-tetrahydrofuran complex. The product is alkylated with an alkyl halide under the influence of a base such as sodium hydride or potassium carbonate to give a further derivative or acylated with a carboxylic acid derivative,
Subsequently, the amide may be reduced under the conditions described above to give further derivatives.

The following non-limiting specific examples are provided to illustrate the synthetic methods used to prepare the compounds of Formula A. In these examples, all reactants and intermediates are either commercially available, can be prepared by standard methods found in the literature, or are known to those skilled in the art of organic synthesis. Some preferred embodiments are described to illustrate the invention. However, it should be understood that the invention is not limited to particular embodiments.

Intermediate 1 N-tert-butoxycarbonyl- [1- (2-methoxyphenyl) piperazine] -4-isonipecotamide 4- (2-methoxyphenyl) piperazine hydrochloride (5.0 g, 21.8 Mmol)
DAEC (4.18 g, 21.8 mmol) in DMF (35 mL), HOBT
(1.3 eq, 3.83 g, 28.3 mmol) and Nt-butoxycarbonylisonipecotic acid (5 g, 21.8 mmol) and the resulting solution was treated with NM.
M (2.5 eq, 6.0 mL, 54.5 mmol) and stirred at 0 ° C. for 16 h. Water (100 mL) was added, the product was extracted with ethyl acetate (3 × 50 mL), and the combined organics were washed with 1N HCl (20 mL), saturated NaHCO ₃ (25 mL),
It was dried over anhydrous sodium sulfate. Filtration and concentration under vacuum provided the product as a white solid (8.79 g, 99% yield). Elemental analysis _{(as C 22 H 33 N 3 O 4} ): Calculated: C, 65.48; H, 8.24 ; N, 10.41 Found: C, 65.23; H, 8.15 N, 10.23

Intermediate 2 1- (2-methoxyphenyl) piperazine-4-isonipecotoamide Carbamate of intermediate 1 (8.79 g, 21.8 mmol) was converted to 4M HC
Dissolved in 1-dioxane (40 mL) and the solution was stirred at ambient temperature for 6 hours. The mixture was concentrated in vacuo, ethyl ether (50 mL) was added, and the precipitated product was collected by filtration, washed with ether (50 mL) and a white solid (7.28 g)
, Yield 98%). Elemental analysis _{(as C 17 H 26 N 3 O 2} ): Calculated: C, 60.08; H, 7.71 ; N, 10.43 Found: C, 59.99; H, 7.56 N, 10.23

Intermediate 3 N-tert-butoxycarbonyl- [1- (2-methoxyphenyl) piperazine] -4-nipecotamide 4- (2-methoxyphenyl) piperazine hydrochloride (5.0 g, 21.8 mmol) ,
DAEC (4.18 g, 21.8 mmol) in DMF (35 mL), HOBT
(1.3 equivalents, 3.83 g, 28.3 mmol) and Nt-butoxycarbonyl nipecotic acid (5 g, 21.8 mmol) and the resulting solution was added to NMM (21.8 mmol).
(0.5 eq, 6.0 mL, 54.5 mmol) and stirred at 0 ° C. for 16 h. water
(100 mL) was added, the product was extracted with ethyl acetate (3 × 50 mL), and the combined organics were washed with 1N HCl (20 mL), saturated NaHCO ₃ (25 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under vacuum provided the product as a white solid (8.79 g, 99% yield). Elemental analysis _{(as C 22 H 33 N 3 O 4} ): Calculated: C, 65.48; H, 8.24 ; N, 10.41 Found: C, 65.45; H, 8.23 N, 10.32.

Intermediate 4 1- (2-methoxyphenyl) piperazine-4-nipecotamide Carbamate of intermediate 3 (8.79 g, 21.8 mmol) was converted to 4M HC
Dissolved in 1-dioxane (40 mL) and the solution was stirred at ambient temperature for 6 hours. The mixture was concentrated in vacuo, ethyl ether (50 mL) was added, and the precipitated product was collected by filtration, washed with ether (50 mL) and a white solid (7.28 g)
, Yield 98%). Elemental analysis _{(as C 17 H 26 N 3 O 2} ): Calculated: C, 60.08; H, 7.71 ; N, 10.43 Found: C, 60.22; H, 7.56 N, 10.39

Example 1 1- (2-Methoxyphenyl) -4-piperidin-4-ylmethylpiperazine Amide of intermediate 2 (7.28 g, 21.8 mmol) in THF (100 mL) and triethylamine (6 mL) Of borane-THF at 0 ° C. under nitrogen.
(1.0 M, 76 mL) was added dropwise. The mixture was refluxed for 16 hours at 0 ° C.
After cooling to, the reaction was quenched by adding 2N HCl (50 mL). After stirring for 1 hour, the solution was made basic with NaOH and the product was ethyl acetate (
3 × 35 mL). Combine organics with water (50 mL), brine (50 mL)
And dried over anhydrous sodium sulfate. Filtration and concentration under vacuum provided the desired product (4.4 g, 78% yield). A solution of the product in ethanol was treated with a hot ethanol solution of fumaric acid (1.0 eq) to give the fumarate of the title compound as a light yellow solid. M ⁺ = 289 Elemental analysis _{(as C 17 H 27 N 3 O ·} 1.0C 4 H 4 O 4 · 1.1H 2 O): Calculated: C, 59.30; H, 7.87 ; N , 9.88 Found: C, 58.80; H, 7.63; N, 10.34.

Example 2 Cyclohexyl- {4- [4- (2-methoxyphenyl) piperazin-1-ylmethyl]
Piperidin-1-yl} methanone cyclohexanecarbonyl chloride (0.506 g, 3.5 mmol), of Example 1 in the _{CH 2 Cl 2 (30mL) 1-} (2- methoxyphenyl) -4-piperidin-4 Ilmethylpiperazine (1.0 g, 3.5 mmol) and triethylamine
(2 eq, 1 mL) and the solution was stirred at 0 ° C. under nitrogen for 16 hours.
The mixture was concentrated in vacuo, water (50 mL) was added and the product was added to ethyl acetate (3 ×
25 mL). The combined organics were washed with water (25mL), saturated sodium bicarbonate solution (20mL) and brine (25mL). After drying over sodium sulfate, filtering and concentrating in vacuo, the title product was obtained (0.765 g, 5% yield).
5%). A solution of the product in ethanol was treated with a hot ethanol solution of fumaric acid (1.0 eq) to give the fumarate of the title compound as a light yellow solid. M ⁺ = 399 Results of elemental analysis (as C ₂₄ H ₃₇ N ₃ O ₂ .1.0 C ₄ H ₄ O ₄ ): Calculated: C, 65.22; H, 8.01; N, 8.15 Values: C, 65.00; H, 8.19; N, 8.18

Example 3 1- (1-Cyclohexylmethylpiperidin-3-ylmethyl) -4- (2-methoxyphenyl) piperazine Borane-THF (1.0 M, 4 mmol) was performed under nitrogen at 0 ° C. 1- (2) of Example 1
-Methoxyphenyl) -4-piperidin-4-ylmethylpiperazine (0.382 g, 0
(.957 mmol) in a THF solution. The mixture was refluxed for 16 hours at 0 ° C.
After cooling to, the reaction was quenched by adding 2N HCl (50 mL). After stirring for 1 hour, the solution was made basic with NaOH and the product was ethyl acetate (
3 × 35 mL). Combine organics with water (50 mL), brine (50 mL)
And dried over anhydrous sodium sulfate. Filter and concentrate under vacuum to give the desired product (0.19 g, 51% yield). Fumaric acid (ethanol solution of the product
(2.0 eq.) Of hot ethanol solution to give the fumarate of the title compound as a light yellow solid. M ⁺ = 385 Elemental analysis (as C ₂₄ H ₃₇ N ₃ O ₂ · 1.0 C ₄ H ₄ O ₄ ): Calculated: C, 62.22; H, 7.67; N, 6.80. Values: C, 62.25; H, 7.50; N, 6.92

Example 4 {4- [4- (2-Methoxyphenyl) piperazin-1-ylmethyl] piperidin-1-yl} phenylmethanone Benzoyl chloride (0.49 g, 3.5 mmol) was added to CH ₂ Cl _{2 to} a solution of 1- (2-methoxyphenyl) -4-piperidin-4-ylmethylpiperazine (1.0 g, 3.5 mmol) and triethylamine (2 equiv, 1 mL) of Example 1 in (30 mL). The solution was stirred at 0 ° C. for 16 hours under nitrogen. The mixture was concentrated under vacuum, water (50 mL) was added, and the product was extracted with ethyl acetate (3 × 25 mL).
The combined organics were washed with water (25mL), saturated sodium bicarbonate solution (20mL) and brine (25mL). After drying over sodium sulfate, filtration and concentration in vacuo gave the title product (0.91 g, 66% yield). A solution of the product in ethanol was treated with a hot ethanol solution of fumaric acid (1.0 eq) to give the fumarate of the title compound as a light yellow solid. M ⁺ = 393 Elemental analysis (as C ₂₄ H ₃₁ N ₃ O ₂ .1.0 C ₄ H ₄ O ₄ ): Calculated: C, 65.99; H, 6.92; N, 8.25. Values: C, 66.17; H, 6.91; N, 8.30

Example 5 1- (1-benzylpiperidin-4-ylmethyl) -4- (2-methoxyphenyl) piperazine 4- (2-methoxyphenyl) piperazine hydrochloride (1.0 g, 4.35 mmol) ,
DAEC (0.83 g, 4.35 mmol) in DMF (15 mL), HOBT
(1.5 equivalents, 0.88 g) and N-benzoylisonipecotic acid (1 g, 4.35 g).
Mmol) and the resulting solution was treated with NMM (2.5 eq, 1.2 mL) and stirred at 0 ° C. for 16 hours. Water (50 mL) was added and the product was washed with ethyl acetate (3
× 50 mL) and the combined organics were washed with 1N HCl (10 mL), saturated NaHC
Washed with O ₃ (15 mL) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the desired amide product as a white solid (1.77 g, 88 yield).
%). M ⁺ = 407 Result of elemental analysis (as C ₂₄ H ₂₉ N ₃ O ₃ ): Calculated: C, 70.74; H, 7.10; N, 10.31 Found: C, 70.40; H , 7.21; N, 10.37 A solution of the above bis-amide (1.56 g, 3.8 mmol) in THF (25 mL) was stirred at 0 ° C. under nitrogen and hydrogen in THF (38 mL, 10 equiv) was added. The solution was treated dropwise with a 1 M solution of lithium aluminum chloride. Once the addition was complete, the reaction mixture was refluxed for 16 hours. After cooling to 0 ° C., the excess hydride reagent was destroyed by adding saturated ammonium chloride solution, the mixture was filtered, and the filtrate was washed with ethyl acetate (50 mL). The organic solution was washed with water (2 × 50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. The amine was obtained by filtration and concentration. This was treated with ethanolic HBr to give the salt of the title compound as a yellow solid (0.67 g). M ⁺ = 379 Elemental analysis _{(as C 24 H 33 N 3 O ·} 2.0HBr · 1.25H 2 O): Calculated: C, 51.12; H, 6.70 ; N, 7.45 Found Values: C, 50.72; H, 6.31; N, 7.34

Example 6 1- (2-Methoxyphenyl) -4-piperidin-3-ylmethylpiperazine Amide of intermediate 4 in THF (100 mL) (7.4 g, 21.8 mmol)
And triethylamine (6 mL) at 0 ° C. under nitrogen in borane-THF (1 mL).
(0.0M, 76 mL) was added dropwise. The mixture was refluxed for 16 hours, cooled to 0 ° C., and quenched by adding 2N HCl (50 mL). 1
After stirring for an hour, the solution was made basic with NaOH and the product was washed with ethyl acetate (3 ×
35 mL). The combined organics were washed with water (50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under vacuum provided the desired product (4.6 g, 81% yield). A solution of the product in ethanol is treated with a solution of fumaric acid (1.0 equivalent) in hot ethanol to give 1- (2-methoxyphenyl) -4-.
The fumarate of piperidin-3-ylmethylpiperazine was obtained as a light yellow solid. M ⁺ = 289 Elemental analysis _{(as C 17 H 27 N 3 O ·} 1.0C 4 H 4 O 4 · 2.0H 2 O): Calculated: C, 57.13; H, 7.99 ; N , 9.52 Found: C, 57.09; H, 7.84; N, 9.97.

Example 7 Cyclohexyl- {3- [4- (2-methoxyphenyl) piperazin-1-ylmethyl]
Piperidin-1-yl} methanone cyclohexanecarbonyl chloride (0.506 g, 3.5 mmol) was added to 1- (2-methoxyphenyl) -4-piperidin-3- according to Example 6 in CH ₂ Cl ₂ (30 mL). Ilmethylpiperazine (1.0 g, 3.5 mmol) and triethylamine
(2 eq, 1 mL) and the solution was stirred at 0 ° C. under nitrogen for 16 hours.
The mixture was concentrated in vacuo, water (50 mL) was added and the product was added to ethyl acetate (3 ×
25 mL). The combined organics were washed with water (25mL), saturated sodium bicarbonate solution (20mL) and brine (25mL). After drying over sodium sulfate, filtration and concentration in vacuo gave the title product (1.13 g, 81% yield).
%). A solution of the product in ethanol was treated with a hot ethanol solution of fumaric acid (1.0 eq) to give the fumarate of the title compound as a light yellow solid. M ⁺ = 399 Results of elemental analysis (as C ₂₄ H ₃₇ N ₃ O ₂ .1.0 C ₄ H ₄ O ₄ ): Calculated: C, 65.22; H, 8.01; N, 8.15 Values: C, 65.35; H, 8.23; N, 8.01

Example 8 {3- [4- (2-Methoxyphenyl) piperazin-1-ylmethyl] piperidin-1-yl} phenylmethanone Benzoyl chloride (0.49 g, 3.5 mmol) was added to CH ₂ Cl _{2 to} a solution of 1- (2-methoxyphenyl) -4-piperidin-3-ylmethylpiperazine (1.0 g, 3.5 mmol) and triethylamine (2 eq, 1 mL) of Example 6 in (30 mL). The solution was stirred at 0 ° C. for 16 hours under nitrogen. The mixture was concentrated under vacuum, water (50 mL) was added, and the product was extracted with ethyl acetate (3 × 25 mL).
The combined organics were washed with water (25mL), saturated sodium bicarbonate solution (20mL) and brine (25mL). After drying over sodium sulfate, filtration and concentration under vacuum gave the title product (1.08 g, 79% yield). Treatment of the enol solution of the product with a solution of fumaric acid (1.0 eq) in hot ethanol gave the fumarate of the title compound as a light yellow solid. M ⁺ = 393 Elemental analysis _{(as C 24 H 31 N 3 O 2} · 0.75C 4 H 4 O 4): Calculated: C, 67.48; H, 7.13 ; N, 8.74 Found Values: C, 67.76; H, 7.11; N, 8.88

Example 9 1- (1-Benzylpiperidin-3-ylmethyl) -4- (2-methoxyphenyl) piperazine Borane-THF (1.0 M, 4 mmol) was prepared at 0 ° C. under nitrogen at 0 ° C. Eight {3- [
4- (2-Methoxyphenyl) piperazin-1-ylmethyl] piperidin-1-yl} phenylmethanone (0.54 g, 1.37 mmol) was added dropwise to a THF solution (8 mL).
The mixture was refluxed for 16 hours, cooled to 0 ° C., and quenched by adding 2N HCl (50 mL). After stirring for 1 hour, the solution was basified with NaOH and the product was extracted with ethyl acetate (3 × 35 mL). The combined organics were washed with water (50 mL), brine (50 mL) and dried over anhydrous sodium sulfate.
Filter and concentrate under vacuum to give the desired product (0.36 g, 69% yield). Treating an ethanol solution of the product with a hot ethanol solution of fumaric acid (2.0 equiv.)
The fumarate of the title compound was obtained as a light yellow solid. M ⁺ = 379 Elemental analysis _{(as C 24 H 33 N 3 O ·} 1.0C 4 H 4 O 4 · 1H 2 O)
: Calculated: C, 64.91; H, 7.69; N, 8.11 Found: C, 64.70; H, 7.37; N, 8.06

Example 10 Example 6 in 3- (2- {3- [4- (2-methoxyphenyl) piperazin-1-ylmethyl] piperidin-1-yl} ethyl) -1H-indole acetonitrile (25 mL) 1- (2-methoxyphenyl)-
4-piperidin-3-ylmethylpiperazine (0.5 g, 1.72 mmol), 3- (2-
(Bromoethyl) indole (0.38 g, 1 equivalent) and potassium carbonate (0.48 g,
(2 equivalents) was refluxed for 24 hours under a nitrogen atmosphere. Add water (100 mL)
The product was extracted with ethyl acetate (3x50mL). Combine organics with water (25 mL)
, And washed with brine (25 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under vacuum provided the desired product. Treatment with excess ethanolic HCl gave the hydrochloride salt of the title compound as a white solid. M ⁺ = 432 Elemental analysis result (as C ₂₇ H ₃₆ N ₄ O · 2.0 HCl · 1H ₂ O): Calculated: C, 61.94; H, 7.70; N, 10.70 Found: C, 61.82; H, 7.41; N, 10.36

Example 11 [4- (1H-Indol-4-yl) piperazin-1-yl] piperidin-4-ylmethanone 4- (Indol-4-yl) piperazine (1.75 g, 8.7 mmol) , DMF (
DAEC (1.67 g, 1 eq), HOBT (1.3 eq, 1.
53 g) and N-butoxycarbonylisonipecotic acid (2 g, 8.7 mmol)
And the resulting solution was treated with NMM (1.5 eq, 1.5 mL),
For 16 hours. Water (100 mL) was added and the product was washed with ethyl acetate (3 × 50 m
L), the combined organics were combined with 1N HCl (20 mL), saturated NaHCO ₃ (2
5 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under vacuum provided the product as a white solid (3.07 g, 85% yield). A sample of this carbamate (1.5 g, 3.63 mmol) was dissolved in 4 M HCl-dioxane (20 mL) and the solution was stirred at ambient temperature for 4 hours. The mixture was concentrated in vacuo, diethyl ether (50 mL) was added, and the precipitated product was collected by filtration, washed with ether (50 mL), and a tan solid (1.2 g, 98% yield). ). Melting point> 240 ° C. M ⁺ = 313 Elemental analysis results (as C ₁₈ H ₂₄ N ₄ O.2HCl): Calculated: C, 56.10; H, 6.80; N, 14.54 Found: C, 55.76; H, 6.65; N, 14.11.

Example 12 4- [4- (1-Methylpiperidin-4-ylmethyl) piperazin-1-yl] -1H-indole Carbamate of Example 11 in THF (20 mL) using a nitrogen atmosphere (1.5 g, 3.63 mmol) at 0 ° C. in THF (35 mL, 1 mL).
(1.0 eq) of lithium aluminum hydride in 0.1 M) was added dropwise and the solution was refluxed for 16 hours. After cooling to ambient temperature, the excess hydride was destroyed by adding ammonium chloride solution and the mixture was filtered. Ethyl acetate(
(50 mL), and the solution was washed with water (50 mL), brine (25 mL) and dried over anhydrous sodium sulfate. Filtration and concentration gave the title product. This was converted to its hydrochloride salt by the action of ethanolic HCl. M ⁺ = 312 Results of elemental analysis (as C ₁₉ H ₂₈ N ₄ .1HCl.0.5H ₂ O): Calculated: C, 63.76; H, 8.45; N, 15.65 Found: C H, 8.31; N, 15.43.

The compounds of the present invention bind with very high affinity to the 5-HT1A receptor, so that they are affected by central nervous system disorders such as depression, anxiety, sleep disorders, sexual dysfunction It is useful for treating addiction to alcohol and cocaine, cognitive deficits and related problems, as well as treating Alzheimer's disease, Parkinson's disease, obesity and migraine.

5-HT1A Receptor Binding Assay High affinity for serotonin 5-HT1A receptor displaces [ ³ H] 8-OH-DPAT binding in CHO cells stably transfected with human 5-HT1A receptor. It was established by measuring the potency of the claimed compounds. Stably transfected CHO cells are grown in DMEM containing 10% heat-inactivated FBS and non-essential amino acids. Cells are scraped from the plate, transferred to a centrifuge tube, and centrifuged (200 mM) in buffer (50 mM Tris, pH 7.5).
(0 rpm, 4 minutes at 4 ° C.). The resulting pellet is aliquoted and stored at -80 ° C. On the day of the assay, thaw these cells on ice,
Resuspend in buffer. The binding assay is performed in a total volume of 250 μL of a 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 incubation at room temperature for 30 minutes, the reaction is terminated by adding ice-cold buffer and rapidly filtering through a GF / B filter pre-soaked in 0.5% PEI for 30 minutes. Compounds are first tested in a single point assay to provide 1, 0.1, and 0.01 mM
, And the Ki value of the active compound is determined.

5-HT1A Receptor Intrinsic Activity Assay The intrinsic activity of the compounds of the present invention reverses the stimulation of cyclic adenosine monophosphate (cAMP) in CHO cells stably transfected with the human 5-HT1A receptor. Established by testing the ability of the compounds described in the range.

[0043] Stably transfected CHO cells were grown in DMEM containing 10% heat-inactivated FBS and non-essential amino acids. Cells are seeded in 24-well plates at a density of × 10 ⁶ cells / well and incubated in a CO ₂ incubator for 2 days. On day 2, the medium was treated with treatment buffer (DMEM + 25 mM HEPE).
S, 5 mM theophylline, 10 μM purgulin) and incubate at 37 ° C. for 10 minutes. After treating the wells with forskolin (final concentration 1 μM), the wells are immediately treated with the test compounds (0.1 and 1 μM for the initial selection) and incubated at 37 ° C. for a further 10 minutes. The medium is removed and the reaction is terminated by adding 0.5 mL of ice-cold assay buffer (supplied with the RIA kit). Plates are stored at -20 <0> C before assessing cAMP formation by RIA. EC ₅₀ values are determined for the active test compound. No agonist activity (
(Emax = 0%) Compounds are further analyzed for their ability to reverse agonist-induced activity. In separate experiments, six concentrations of antagonist are pre-incubated for 20 minutes before adding agonist and forskolin.
Cells are harvested as described above. cAMP kit is supplied by Amersham (Amersham), RIA is performed according to kit instructions, calculation of IC ₅₀ of performed graphically pad Prism (Graph Pad Prism).

[0044]

[Table 1]

Thus, the compounds of the present invention exhibit high affinity for the 5-HT1A receptor subtype and possess intrinsic activity, as evidenced by their ability to reverse the stimulation of cyclic adenosine monophosphate (cAMP). Show. Accordingly, the compounds of the present invention are useful in treating central nervous system disorders and may be administered to patients suffering from one or more of these disorders. As used herein, treatment means reducing or ameliorating the symptoms of a particular disorder in a patient. In addition, the compounds of the invention may be administered as part of a treatment regimen that includes other drugs that affect the central nervous system. In some preferred embodiments, the compounds of the invention are part of a combination therapy that includes a serotonin reuptake inhibitor. Serotonin reuptake inhibitors useful in the combination therapy of the present invention include fluoxetine, fluvoxamine, paroxetine, sertraline,
Venlafaxine and the like. These agents may be administered concurrently with the compounds of the present invention when they are combined in a single dosage form, and may be administered at a different time than the compounds of the present invention while being part of a combination therapy regimen. May be.

The compounds of the present invention may be administered to a patient as such or with a conventional pharmaceutical carrier.

Applicable solid carriers include flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrants1 Species or more substances or encapsulating materials may be mentioned. In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. 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, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melting point wax, ion exchange resin and the like.

[0048] Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of the present invention is a pharmaceutically acceptable liquid carrier, for example,
It can be dissolved or suspended in water, an organic solvent, a mixture of both, a pharmaceutically acceptable fat or oil, and the like. Liquid carriers may contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorants, suspending agents, thickeners, colorants, viscosity modifiers, It may contain stabilizers, osmotic pressure regulators and the like. Suitable examples of liquid carriers for oral and parenteral administration include water (especially additives such as those described above, e.g.,
Cellulose derivatives, preferably containing sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols, such as glycols) and their derivatives, oils (e.g., fractionated coconut oil and peanut oil) and the like. . 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 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.

Preferably, the pharmaceutical composition is in unit dosage form, for example, as a tablet or capsule. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged composition, for example,
It can be a vial, ampule, filled syringe or liquid bag. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions packaged.

[0051] The therapeutically effective amount to be used specifically for the treatment of psychosis must be subjectively determined by the attending physician. Relevant variables include the particular psychiatric or anxiety state, the physique, age and response pattern of the patient. A novel method of the present invention for treating a disease associated with or affected by the 5-HT1A receptor is disclosed in a warm-blooded animal, including humans, in an effective amount of a compound of formula A or a non-toxic pharmaceutical. Administering at least one compound represented by the acceptable addition salt. These compounds may be administered orally, rectally, parenterally, or topically on the skin or mucous membranes. The usual daily dose depends on the particular compound, the method of treatment and the disease to be treated. The usual daily dose is 0.01 to 1000 mg / kg, preferably 0.5 to 500 mg / kg for oral administration and 0.1 to 100 mg / kg for parenteral administration.
g / kg, preferably 0.5 to 50 mg / kg.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4525 A61K 31/4525 31/496 31/496 A61P 3/04 A61P 3/04 15/10 15 / 10 25/06 25/06 25/16 25/16 25/20 25/20 25/22 25/22 25/24 25/24 25/28 25/28 25/30 25/30 25/32 25/32 43 / 00 111 43/00 111 114 114 C07D 401/06 C07D 401/06 401/12 401/12 (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, TZ, UG, ZW) EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, C R, CU, CZ, DE, DK, DM, 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, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI , SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Ivet Latco Palmer South Ridge, Yadley, PA 19067 USA 542th F term (reference) 4C054 AA02 CC 01 CC02 CC04 DD01 EE01 EE04 EE16 FF01 FF04 FF16 4C063 AA01 BB03 CC10 DD06 EE01 4C086 AA01 AA02 AA03 BC21 BC50 GA02 GA07 GA12 MA01 MA02 MA04 MA10 NA14 ZA02 ZA05 ZA08 ZA12 ZA15 ZA81 ZAA ZAA ZAC MA01 MA02 MA04 NA14 ZA02 ZA05 ZA08 ZA12 ZA15 ZA16 ZA70 ZA81 ZC14 ZC39 ZC41 ZC75

Claims (28)

[Claims] (1) Formula (A): Wherein R ₁ is aryl or heteroaryl; A is NR ₂ or CH ₂ , B is NR ₂ or CH ₂ (where A is not the same as B); R ₂ is hydrogen, alkyl, cycloalkyl , Alkylcycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, aryl, aralkyl, heteroaryl, alkylheteroaryl or COR ₃ ; R ₃ is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Or an integer of 0 to 2] or a pharmaceutical salt thereof. Wherein R ₁ is phenyl; 2-, 3- or 4-pyridyl; 2-pyrimidyl; benzodioxan-5-yl; indol-4-yl; 3-thienyl; is 1- or 2-naphthyl wherein Item 7. The compound according to Item 1. 3. The compound according to claim 1, wherein R ₁ is substituted by phenyl or indol-4-yl. 4. The method of claim 1 to 3 R ₂ is aralkyl, alkyl cycloalkyl, alkyl heteroaryl, alkyl heterocycloalkyl, or COR ₃
The compound according to any one of the above. 5. The compound according to claim 1, wherein R ₁ is phenyl or indol-4-yl, R ₂ is COR ₃ , and R ₃ is cyclohexyl, phenyl or piperazin-4-yl. 6. The compound according to claim 1, which is 1- (2-methoxyphenyl) -4-piperidin-4-ylmethylpiperazine or a pharmaceutically acceptable salt thereof. 7. Cyclohexyl- {4- [4- (2-methoxyphenyl) piperazine
The compound according to claim 1, which is [-1-ylmethyl] piperidin-1-yl} methanone or a pharmaceutical salt thereof. 8. 1- (1-Cyclohexylmethylpiperidin-3-ylmethyl)-
The compound according to claim 1, which is 4- (2-methoxyphenyl) piperazine or a pharmaceutical salt thereof. 9. 4- (4- (2-methoxyphenyl) piperazin-1-ylmethyl]
The compound according to claim 1, which is piperidin-1-yl} phenylmethanone or a pharmaceutical salt thereof. 10. The compound according to claim 1, which is 1- (1-benzylpiperidin-4-ylmethyl) -4- (2-methoxyphenyl) piperazine or a pharmaceutical salt thereof. 11. The compound according to claim 1, which is 1- (2-methoxyphenyl) -4-piperidin-3-ylmethylpiperazine or a pharmaceutical salt thereof. 12. The compound according to claim 1, which is cyclohexyl- {3- [4- (2-methoxyphenyl) piperazin-1-ylmethyl] piperidin-1-yl} methanone or a pharmaceutical salt thereof. (13) {3- [4- (2-methoxyphenyl) piperazin-1-ylmethyl)
] The compound according to claim 1, which is piperidin-1-yl} phenylmethanone or a pharmaceutical salt thereof. 14. The compound according to claim 1, which is 1- (1-benzylpiperidin-3-ylmethyl) -4- (2-methoxyphenyl) piperazine or a pharmaceutically acceptable salt thereof. 15. The method according to claim 1, which is 3- (2- {3- [4- (2-methoxyphenyl) piperazin-1-ylmethyl] piperidin-1-yl} ethyl) -1H-indole or a pharmaceutical salt thereof. A compound as described. 16. The compound according to claim 1, which is [4- (1H-indol-4-yl) piperazin-1-yl] piperidin-4-ylmethanone or a pharmaceutical salt thereof. 17. A method for preparing 4- [4- (1-methylpiperidin-4-ylmethyl) piperazine.
The compound according to claim 1, which is [-1-yl] -1H-indole or a pharmaceutical salt thereof. 18. A method of treating a patient suffering from a central nervous system disorder associated with the 5-hydroxytryptamine 1A receptor subtype, comprising a therapeutically effective amount of a formula.
(A): embedded image Wherein R ₁ is aryl or heteroaryl; A is NR ₂ or CH ₂ , B is NR ₂ or CH ₂ (where A is not the same as B); R ₂ is hydrogen, alkyl, cycloalkyl , Alkylcycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, aryl, aralkyl, heteroaryl, alkylheteroaryl or COR ₃ ; R ₃ is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Or an integer of 0 to 2] or a pharmaceutical salt thereof. 19. The method according to claim 18, wherein the disorder is depression, anxiety or depression. 20. The method of claim 18, wherein the disorder is a sleep disorder or sexual dysfunction. 21. The disorder according to claim 1, wherein the disorder is addiction to a drug or alcohol.
8. The method according to 8. 22. The method of claim 18, wherein the disorder is a cognitive disorder. 23. The method of claim 18, wherein the disorder is a neurodegenerative disease. 24. The method according to claim 23, wherein the neurodegenerative disease is Parkinson's disease or Alzheimer's disease. 25. The method of claim 18, wherein the disorder is migraine. 26. The method according to claim 18, wherein the disorder is obesity. 27. The method of claim 18, further comprising administering a serotonin reuptake inhibitor. 28. The method of claim 27, wherein the serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine.