Eureka AIR delivers breakthrough ideas for toughest innovation challenges, trusted by R&D personnel around the world.

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
View PDF11 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[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 neurotransmitter in the synapse, as well as its duration therein, which together influence the magnitude of synaptic transmission. Further, by preventing the spread of transmitter to neighboring synapses, transporters maintain the fidelity of synaptic transmission. Last, by sequestering released transmitter into the presynaptic terminal, transporters allow for transmitter reutilization.
[0005] The amino acid glycine is a major neurotransmitter in the mammalian central nervous system, functioning at both inhibitory and excitatory synapses. By nervous system, both the central and peripheral portions of the nervous system are intended. These distinct functions of glycine are mediated by two different types of receptor, each of which is associated with a different class of glycine transporter. The inhibitory actions of glycine are mediated by glycine receptors that are sensitive to the convulsant alkaloid strychnine, and are thus referred to as “strychnine-sensitive.” Such receptors contain an intrinsic chloride channel that is opened upon binding of glycine to the receptor; by increasing chloride conductance, the threshold for firing of an action potential is increased. Strychnine-sensitive glycine receptors are found predominantly in the spinal cord and brainstem, and pharmacological agents that enhance the activation of such receptors will thus increase inhibitory neurotransmission in these regions.
[0008] Compounds that inhibit or activate glycine transporters would thus be expected to alter receptor function, and provide therapeutic benefits in a variety of disease states. For example, inhibition of GlyT-2 can be used to diminish the activity of neurons having strychnine-sensitive glycine receptors via increasing synaptic levels of glycine, thus diminishing the transmission of pain-related (i.e., nociceptive) information in the spinal cord, which has been shown to be mediated by these receptors. Yaksh, Pain. 37, 111-123 (1989). Additionally, enhancing inhibitory glycinergic transmission through strychnine-sensitive glycine receptors in the spinal cord can be used to decrease muscle hyperactivity, which is useful in treating diseases or conditions associated with increased muscle contraction, such as spasticity, myoclonus, and epilepsy (Truong et al. Movement Disorders, 3, 77-87 (1988); Becker, FASEB J., 4, 2767-2774 (1990)). Spasticity that can be treated via modulation of glycine receptors is associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord injury, dystonia, and other conditions of illness and injury of the nervous system.

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 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.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
temperaturesaaaaaaaaaa
temperaturesaaaaaaaaaa
temperatureaaaaaaaaaa
Login to View More

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
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
CPCA61K31/198C07F9/3808A61K31/445C07C229/14C07C229/16C07C237/06C07C255/43C07C303/40C07C2103/18C07C2103/32C07C2103/74C07C2103/88C07D205/04C07D207/16C07D209/02C07D209/42C07D211/60C07D213/65C07D223/28C07D257/04C07D279/24C07D279/26C07D295/03C07D295/073C07D295/088C07D307/14C07D307/42C07D317/64C07D333/20A61K31/216A61P25/00C07C2603/18C07C2603/32C07C2603/74C07C2603/88
Inventor OGNYANOV, VASSIL ILIYABORDEN, LAURENCE A.BELL, STANLEY CHARLESZHANG, JIN
Owner NPS PHARM INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Eureka Blog
Learn More
PatSnap group products