Dual modulators of 5HT2a and d3 receptors

a technology of d3 receptor and modulator, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, biocide, etc., can solve the problems of reduced patient quality of life and socioeconomic problems, less effective treatment of negative symptoms, and reduced patient compliance, and achieves high affinity for d3

Inactive Publication Date: 2009-01-29
F HOFFMANN LA ROCHE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0048]The compounds of the invention have high affinity for the dopamine D3 and serotonin (5-Hydroxytryptamine; 5-HT) 5-HT2A receptors and are effective in the treatment of psychotic disorders, as well as other diseases such as depression and anxiety, dru

Problems solved by technology

These antipsychotics, although relatively successful (some patients exhibit treatment resistance) at treating the positive symptoms of schizophrenia, are less effective at treating negative symptoms, cognitive deficits, and associated depression and anxiety, all of whi

Method used

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  • Dual modulators of 5HT2a and d3 receptors
  • Dual modulators of 5HT2a and d3 receptors
  • Dual modulators of 5HT2a and d3 receptors

Examples

Experimental program
Comparison scheme
Effect test

example 1

4N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide

Intermediate B

Trans-(4-amino-cyclohexyl)-acetic acid ethyl ester

Step 1

[0358](4-Nitro-phenyl)-acetic acid (50g, 276 mmol) was added to a stirred solution of 22.08g of 50% sodium hydroxide solution in 450 mL deionizated water. The clear yellow solution is transferred into a high-pressure autoclave that it charged with 30 g (511 mmol) of water-wet sponge nickel catalyst. The autoclave is sealed, flushed with nitrogen and then pressurized to 115 bar with hydrogen. The reaction mixture is stirred and heated to 125° C. for 48 h. At that time the autoclave is cooled, vented and charged under nitrogen with another 30 g (511 mmol) of the sponge nickel catalyst. The autoclave is flushed again with nitrogen and then pressurized to 115 bar and the vessel is heated to 130° C. while stirring (a maximum pressure of 130 bars is observed). Hydrogenation is continued for 5 days to 130° C. The autoclave is t...

example 2

Tetrahydro-pyran-4-carboxylic acid trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide

[0365]Tetrahydro-pyran-4-carboxylic acid (0.013 g, 0.096 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate (0.026 g, 0.08 mmol) and (0.04 mL, 0.24 mmol) of N-ethyldiisopropylamine were stirred in 0.6 mL of DMF for 0.5 h at room temperature and Trans 4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexlamine (could be obtained as the trifluoroacetic acid salt) (trifluoro acetic acid salt) (0.030 g, 0.08 mmol) was added. The mixture was stirred for 12 hours at room temperature. The mixture was concentrated to dryness and the residue was taken up on methanol and purified with preparative HPLC on reversed phase eluting with acetonitrile / water. The combined producted fractions were evaporated under reduced pressure to yield 0.027 g of a off-white solid (0.06 mmol, 74%). MS (m / e): 458.5 (M+H+).

[0366]According to the proce...

example 24

N-trans(4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide

Intermediate E

Trans (4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester

[0367]A mixture of 5-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.3 g, 5 mmol), trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (example 1, intermediate C) (1.6 g, 6 mmol), triethylamine (0.64 mL, 5 mmol) in 1, 2 dichloroethane (27 mL) was stirred for 4 h at room temperature and sodium triacetoxyborohydride (1.9 g, 9 mmol) was added slowly and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2—CH2Cl2 / MeOH (1-9:1). The product fractions were concentrated to give 2.3 g (5.1 mmol, 100% yield) of a off-white solid. MS (m / e): 446.3 (M+H+).

Intermediate F

Trans 4-{2-[4-(5-Fluoro-benzo[d]is...

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PUM

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Abstract

The present invention relates to compounds of the formula (I)
wherein R1, R2, X and n are as defined in the specification as dual modulators of the serotonin 5-HT2a and dopamine D3 receptors, their manufacture, pharmaceutical compositions containing them and their use for the treatment of psychotic disorders, as well as other diseases such as depression and anxiety, drug dependence, dementias and memory impairment.

Description

PRIORITY OF RELATED APPLICATION(S)[0001]This application claims the benefit of European Patent Application No. 07113252.6, filed Jul. 26, 2007, which is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION[0002]Schizophrenia is characterized by complex symptomatology including positive symptoms, (i.e. delusions and hallucinations), and negative symptoms, (i.e. anhedonia, restricted fluency and productivity of thought and speech). In addition it is now well recognized that cognitive impairment is the third major diagnostic category of schizophrenia, characterized by loss in working memory as well as other deficits. Other symptoms include aggressiveness, depression and anxiety (Stahl, S. M. (2000) Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. Cambridge University Press, second edition, Cambridge, UK). The different categories and the clinical features of the disorder are defined in diagnostic schemes such as DSM-IV (Diagnostic ...

Claims

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Application Information

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IPC IPC(8): A61K31/454C07D261/20C07D413/14A61K31/541A61P25/18A61K31/5377C07D279/12
CPCC07D413/04C07D417/14C07D413/14A61P25/00A61P25/08A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P25/36
Inventor GOBBI, LUCAJAESCHKE, GEORGROCHE, OLIVIERRODRIGUEZ SARMIENTO, ROSA MARIASTEWARD, LUCINDA
Owner F HOFFMANN LA ROCHE INC
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