Bicyclic [3.1.0.] heteroaryl amides as type 1 glycine transport inhibitors

a heteroaryl amide and bicyclic technology, applied in the field of bicyclic3 . 1 . 0heteroaryl amides, can solve the problems of ignoring the negative and cognitive aspects of cns, one of the most costly of all diseases, and the cost of cns diseas

Inactive Publication Date: 2006-10-12
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0014] wherein R7 and R8 independently represent H, (C1-C8)alkyl, (C3-C8)cycloalkyl, (5-10 membered)heterocycloalkyl, (C1-C8)hydroxyalky, (5-10 membered)heteroaryl or (C1-C10)alkoxyalkyl; wherein R7 and R8 may option

Problems solved by technology

The burden on society of this devastating illness and the toll it takes on family members of affected patients make it one

Method used

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  • Bicyclic [3.1.0.] heteroaryl amides as type 1 glycine transport inhibitors
  • Bicyclic [3.1.0.] heteroaryl amides as type 1 glycine transport inhibitors
  • Bicyclic [3.1.0.] heteroaryl amides as type 1 glycine transport inhibitors

Examples

Experimental program
Comparison scheme
Effect test

preparation 1

6-Hydroxymethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0131] To a solution of (3-Aza-bicyclo[3.1.0]hex-6-yl)-methanol-HCl (11.8 gm, 78.7 mmol) in 350 mL of anhydrous CH2Cl2 at room temperature was added Et3N (32.9 mL, 236 mmol), followed by (BOC)2O (18.9 gm, 86.6 mmol) in portions. The reaction was stirred at room temperature for 18 hours. The mixture was washed with saturated NaHCO3, water, brine and dried over anhydrous MgSO4. The mixture was filtered and concentrated under reduced pressure to yield the crude material, which was purified via flash chromatography with 10% MeOH / CH2Cl2. The product containing fractions were collected and concentrated to yield 6-Hydroxymethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (15.6 gm). 400 MHz 1H NMR (CDCl3) δ 3.4-3.6 (m, 4H), 3.2-3.7 (m, 2H), 1.72 (brs, 1H), 1.4-1.4 (m, 10H), 0.9-0.9 (m, 1H); MS (M+1) 213.2.

preparation 2

6-Formyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0132] To a stirring solution of oxalyl chloride (7.8 mL, 89.5 mmol) in 370 mL of anhydrous CH2Cl2 at −78° C., under Nitrogen, was added DMSO (13.8 mL, 193.9 mmol) dropwise. After 10 minutes, 6-Hydroxymethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (15.9 gm, 74.5 mmol) in 72 mL anhydrous CH2Cl2 was added. After the mixture stirred 30 minutes, triethylamine (52.0 mL, 372.9 mmol) was added and the mixture was allowed to slowly warm to 0° C. over 1 hour. The mixture was concentrated, the resulting solid was taken up in saturated NaHCO3 and EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried, filtered and concentrated to give a quantitative crude yield of 6-Formyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (15.8 gm), which was used in the next step without purification. 400 MHz 1H NMR (CDCl3)...

preparation 3

6-[(3-Trifluoromethoxy-benzylamino)-methyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0133] To a stirring solution of the aldehyde prepared above (1.0 g, 4.7 mmol) in 9.5 mL of MeOH was added 3-trifluoromethoxy-benzlyamine (0.7 mL, 4.7 mmol). The reaction mixture was stirred at room temperature for 24 hours. Sodium borohydride (0.4 g, 9.5 mmol) was then added and the reaction mixture stirred for another 24 hours. The reaction was concentrated under reduced pressure and the resulting material was taken up in 1 N NaOH and extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to yield 1.8 gm of the desired amine, which was taken on without purification. 6-[(3-Trifluoromethoxy-benzylamino)-methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 400 MHz 1H NMR (CDCl3) δ 7.3 (t, J=7.8 Hz, 1H), 7.2 (m, 1H), 7.2 (s, 1H), 7.1-7.0 (m, 1H), 3.8 (s, 2H), 3.5 (dd, J=39.4 Hz, 10.8 Hz, ...

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Abstract

The present invention relates to a series of substituted bicyclic[3.1.0]heteroaryl amides of the Formula I, wherein A, Q, X, Y, Z and R1-R5 groups are defined as in the specification, that exhibit activity as glycine transport inhibitors, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their use for the enhancement of cognition and the treatment of the positive and negative symptoms of schizophrenia and other psychoses in mammals, including humans.

Description

CROSS REFERENCE TO RELATED APPLICATION [0001] The present application claims benefit of U.S. Ser. No. 60 / 669,472 filed on Apr. 8, 2005 which is incorporated by reference herein in its entirety.BACKGROUND [0002] The present invention relates to bicyclic[3.1.0]heteroaryl amides and to pharmaceutical compositions containing them and to their use in the treatment of central nervous system disorders, cognitive disorders, schizophrenia, dementia and other disorders in mammals, including humans. These compounds exhibit activity as inhibitors of the glycine type-1 transporter. [0003] Schizophrenia, a progressive neurological disease, is manifested in its early stages as thought disorders such as hallucinations, paranoid delusions, and bizarre thought patterns, collectively known as positive symptoms. These easily recognizable symptoms gave the disease the historical name “madness”. As the disease progresses, negative symptoms, such as social withdrawal and anhedonia, and cognitive symptoms ...

Claims

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Application Information

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IPC IPC(8): C07D403/02A61K31/4178
CPCC07D401/12C07D403/12C07D403/14C07D417/12C07D413/12C07D413/14C07D405/14A61P25/00A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P43/00A61K31/4178
Inventor MCHARDY, STANTON F.LOWE, JOHN A. III
Owner PFIZER INC
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