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Pharmaceutical for treatment of neurological and neuropsychiatric disorders

a neuropsychiatric and drug technology, applied in the direction of drug compositions, group 5/15 element organic compounds, animal repellents, etc., can solve the problem of increasing the likelihood of firing an action potential

Inactive Publication Date: 2006-12-21
NPS PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a group of compounds that inhibit the transport of glycine via the GlyT-1 or GlyT-2 transporters. These compounds can be used as research tools to study the function of these transporters and to develop new drugs that target them. The invention also provides methods for synthesizing these compounds and their precursors. The compounds can be used to treat disorders related to excessive glycine transport, such as hyperglycemia and insulin resistance.

Problems solved by technology

Activation of NMDA receptors increases sodium and calcium conductance, which depolarizes the neuron, thereby increasing the likelihood that it will fire an action potential.

Method used

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  • Pharmaceutical for treatment of neurological and neuropsychiatric disorders
  • Pharmaceutical for treatment of neurological and neuropsychiatric disorders
  • Pharmaceutical for treatment of neurological and neuropsychiatric disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of N-[(4,4-Diphenyl)but-3-enyl]glycine ethyl ester (Compound A26)

[0121] A mixture of 5.95 g (20.7 mmol) 4-bromo-1,1-phenyl-1-butene (prepared as described in F. A. Ali et al., J. Med. Chem., 28: 653-660, 1985), 4.71 g (33.7 mmol) glycine ethyl ester hydrochloride (Aldrich, Milwaukee, Wis.), 11.62 g (84 mmol) potassium carbonate and 1.06 g (6.38 mmol) potassium iodide in 50 ml acetonitrile was refluxed with stirring under argon for seven hours. The reaction mixture was filtered, the solvent evaporated and the residue chromatographed on silica gel column with 20% ethyl acetate in hexanes to give 3.70 g (yield 58%) of N-[(4,4-diphenyl)but-3-enyl]glycine ethyl ester (compound A26) as an oil. NMR spectra of the product showed: 1H NMR (CDCl3, 300 MHz) 7.60-7.00 (m, 10H), 6.09 (t, 1H), 4.16 (q, 2H), 3.35 (s, 2H), 2.71 (t, 2H), 2.32 (dt, 2H), 1.25 (t, 3H), 13C NMR (CDCl3, 75 MHz) 172.29, 143.25, 142.37, 139.82, 129.72, 128.13, 128.04, 127.97, 127.13, 126.92, 126.88, 126.68, 60.56...

example 2

Additional Syntheses According to Reaction 1

[0122] Additional compounds were synthesized using Reaction 1, as follows:

Amino acid orCompoundReagentprecusorSolventYieldA11BX27%A21CX35%A77EX9%A94EX47%A111AX70%A124EX7%A142DX15%A186EX50%A235EX26%A243DY20%A438FX12%A529FX28%A5710FX31%A6711FX10%A7112EX28%A7513FX73%A7714FX36%A8515FX86%A8716FX59%A9017EX16%A9517FX65%A9617EX50%A10415EX62%A10618FX65%A12119EX3%A12219EX40%A12319FX72%A13020EX6%A13221FX90%A13421EX67%A1706FX72%A4822Fx87%A5023FX81%A5324FX76%A5925FX77%A6126FX91%A6327FX91%A7028FX89%A7329FX86%A7430FX76%A7831FX49%A8032FX66%A8233FX38%A8333EX25%A8834FX55%A8935FX75%A9936FX56%A10037FX67%A11138FX34%A11739FX58%A11840FX89%A12041FX62%A12542FX46%A12643EX57%A12744EX5%A12844EX53%A12944FX66%A13845FX48%A14046FX69%A14147FX51%A14248FX67%A14349FX61%A14550FX98%A15551FX70%A15652FX65%A15853FX59%A15954FX85%A16055FX87%A17156FX88%A17357FX81%A17758FX84%A17858FX60%A17959FX68%A18024GX85%

Reagent:

1) 4-bromo-1,1-diphenyl-1-butene, (prepared as described in F. ...

example 3

Synthesis of N-[(3,3-Diphenyl)propyl]glycine ethyl ester (Compound A22)

[0124] 2.132 g (10.1 mmol) 3,3-diphenylpropylamine (Aldrich, Milwaukee, Wis.) was added to a mixture of 0.853 g (5.11 mmol) ethyl bromoacetate (Aldrich) and 2.7 g (19.57 mmol) potassium carbonate in 14 ml acetonitrile at rom temperature. The mixture was stirred under argon for 18 hours. The reaction mixture was filtered, the solvent evaporated and the residue chromatographed on a silica gel column with 40% ethyl acetate in hexanes to give 1.05 g (yield 69%) N-[(3,3-diphenyl)propyl]glycine ethyl ester (Compound A22) as an oil. NMR spectra of the product showed: 1H NMR (CDCl3, 300 MHz) 7.40-7.10 (m, 10H), 4.14 (q, 2H), 4.03 (t, 1H), 3.33 (s, 2H), 2.56 (t, 2H), 2.24 (dt, 2H), 1.22 (t, 3H); 13C NMR (CDCl3, 75 MHz) 172.44, 144.66, 128.43, 127.75, 126.15, 60.63, 50.93, 48.80, 47.92, 35.85, 14.17, 0.019 g of A28 was also isolated from the silica gel column.

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Abstract

The invention provides a pharmaceutical for treatment of neurological and neuropsychiatric disorders comprising a compound of the formula: or a pharmaceutically acceptable salt thereof.

Description

[0001] The present application is a continuation-in-part of: U.S. Ser. No. 08 / 656,063, filed May 31, 1996, U.S. Ser. No. 08 / 655,912, filed May 31, 1996, U.S. Ser. No. 08 / 807,682, filed Feb. 27, 1997, and U.S. Ser. No. 08 / 808,754, filed Feb. 27, 1997, each of which applications are now converted to provisional applications.[0002] The present invention relates to a class of substituted amines, pharmaceutical compositions and methods of treating neurological and neuropsychiatric disorders. [0003] Synaptic transmission is a complex form of intercellular communication that involves a considerable array of specialized structures in both the pre- and post-synaptic neuron. High-affinity neurotransmitter transporters are one such component, located on the pre-synaptic terminal and surrounding glial cells (Kanner and Schuldiner, CRC Critical Reviews in Biochemistry, 22, 1032 (1987)). Transporters sequester neurotransmitter from the synapse, thereby regulating the concentration of neurotransmi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/55A61K31/541A61K31/5377A61K31/496C07D417/02C07D413/02C07D403/02A61K31/198A61K31/216A61K31/445C07C229/14C07C229/16C07C237/06C07C255/43C07C303/40C07D205/04C07D207/16C07D209/02C07D209/42C07D211/60C07D213/65C07D223/28C07D257/04C07D279/24C07D295/02C07D295/03C07D295/073C07D295/088C07D295/092C07D307/14C07D317/64C07D333/20C07F9/38
CPCA61K31/198C07F9/3808A61K31/445C07C229/14C07C229/16C07C237/06C07C255/43C07C303/40C07C2103/18C07C2103/32C07C2103/74C07C2103/88C07D205/04C07D207/16C07D209/02C07D209/42C07D211/60C07D213/65C07D223/28C07D257/04C07D279/24C07D279/26C07D295/03C07D295/073C07D295/088C07D307/14C07D307/42C07D317/64C07D333/20A61K31/216C07C2603/18C07C2603/32C07C2603/74C07C2603/88A61P25/00
Inventor OGNYANOV, VASSIL ILIYABORDEN, LAURENCE A.BELL, STANLEY CHARLESZHANG, JIN
Owner NPS PHARM INC
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