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Branched chain amino acid-dependent aminotransferase inhibitors and their use in the treatment of neurodegenerative diseases

a technology of aminotransferase and branched chain amino acid, which is applied in the direction of biocide, drug composition, metabolic disorder, etc., can solve the problems of neurodegeneration and death, and achieve the effect of preventing neuronal loss

Inactive Publication Date: 2005-01-20
HU LAIN YEN +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Excessive excitation by neurotransmitters can cause the degeneration and death of neurons.

Method used

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  • Branched chain amino acid-dependent aminotransferase inhibitors and their use in the treatment of neurodegenerative diseases
  • Branched chain amino acid-dependent aminotransferase inhibitors and their use in the treatment of neurodegenerative diseases
  • Branched chain amino acid-dependent aminotransferase inhibitors and their use in the treatment of neurodegenerative diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

Benzoic acid, 4-nitro-2-(phenylsulfonyl)hydrazide

A solution of 4-nitro benzoic acid (0.2 g, 1.2 mmol in 10 mL of dry THF) was cooled to 0° C., treated with N-methyl-morpholine (1.6 mL, 14.6 mmol) as well as isobutyl-chloroformate (1.7 mL, 1.3 mmol), and stirred for 10 minutes prior to the addition of benzenesulfonyl hydrazide (0.21 g, 1.2 mmol). After the addition of hydrazide, the mixture was stirred for 3 hours at 25° C. Then the reaction was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution as well as brine, and concentrated in vacuum. The crude material was chromatographed on silica gel eluting with hexanes / ethyl acetate=2:1 to give the desired product (65% yield).

MS: 322.0 (M+1 for C13H11N3O5S1); mp 193-195° C.; TLC (SiO2) Rf=0.74 (8% MeOH / CH2Cl2). HPLC (C18 column, 1:1 CH3CN / H2O+0.1% TFA) 94.95%, RT=5.045 min. HRMS (calc for M+1) 321.0419 (found) 321.0421. IR (KBr, cm−1): 3287, 3067, 2822, 1673, 1520, 1340, 1160, 978. 1H NMR (DMSO-d6)...

example 2

Benzoic acid, 4-amino-2-(phenylsulfonyl)hydrazide

Synthesis of Example 2: Benzoic acid, 4-nitro-2-(phenylsulfonyl)hydrazide (0.82 g, Example 1) was dissolved in 50 mL of THF / EtOH (1:1), treated with wet Raney Nickel (0.6 g) and hydrogenated at 50 psi for 15 hours. The reaction was filtered, concentrated in vacuum, and chromatographed on silica gel eluting with 6% MeOH / CH2Cl2 to give 61 mg (84%) of the desired product.

MS: 291.9 (M+1 for C13H13N3O3S1); mp 171-173° C.; TLC (SiO2) Rf=0.45 (8% MeOH / CH2Cl2); HPLC (C18 column, 1:1 CH3CN / H2O+0.1% TFA) 99.14%, RT=2.575 min. HRMS (calc for M+1) 292.0756 (found) 292.0753. IR (KBr, cm−1): 3471, 3367, 3151, 2925, 1661, 1318, 1162. 1H NMR (DMSO-d6) δ 5.69 (s, 2H), 6.44 (d, 2H, J=8.5 Hz), 7.32-7.58 (m, 5H), 7.75-7.80 (m, 2H), 9.68 (br, 1H), 10.12 (br, 1H).

example 3

Benzoic acid, 4-[[(2,4,6-trichlorophenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide

Benzoic acid, 4-amino-2-(phenylsulfonyl)hydrazide (0.15 g, 0.52 mmol, Example 2) was dissolved in 7 mL of dry pyridine, then 2,4,6-(trichlorophenyl) sulfonyl chloride (0.15 mL, 0.52 mmol) was added, and the reaction was stirred at 25° C. for overnight. The solvent was removed, and the product was recrystalized from ethyl acetate and hexane to give 0.26 g (96%) of the product as a white solid.

MS: 536.0 (M+1 for C19H14Cl3N3O5S2); mp 195.7-196.2° C.; HPLC (C18 column, 1:1 MeCN / H2O+0.1% TFA) 96.3%, RT=8.0 min. 1H NMR (DMSO-D6) δ 7.10 (d, 1H, J=6.8 Hz), 7.40-7.60 (m, 7H), 7.75 (d, 1H, J=7.5 Hz), 7.79 (S, 1H), 8.63 (S, 1H), 9.92 (S, 1H), 10.49 (S, 1H), 11.35 (S, 1H).

EXAMPLE 4

Benzoic acid, 4-[[[4-(trifluoromethyl)phenyl]sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide

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Abstract

The invention relates to BCAT inhibitors and the use thereof for treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome, treating or preventing the adverse consequences of the overstimulation of the excitatory amino acids, treating anxiety, psychosis, convulsions, aminoglycoside antibiotics-induced hearing loss, migraine headache, chronic pain, neuropathic pain, Parkinson's disease, diabetic retinopathy, glaucoma, CMV retinitis, urinary incontinence, opioid tolerance or withdrawal, and inducing anesthesia, as well as for enhancing cognition.

Description

FIELD OF THE INVENTION This invention is related to branched chain amino acid-dependent amino transferase (BCAT) inhibitors. The invention is also directed to the use of BCAT inhibitors as neuro-protective agents for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, anxiety, convulsions, aminoglycoside antibiotics-induced hearing loss, migraine headaches, chronic pain, neuropathic pain, glaucoma, CMV retinitis, diabetic retinopathy, psychosis, urinary incontinence, opioid tolerance or withdrawal, or neuro-degenerative disorders such as lathyrism, Alzheimer's disease, Parkinsonism, amyotrophic lateral sclerosis (ALS), and Huntington's Disease. RELATED BACKGROUND ART Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA) glutamate and aspartate at the N-methyl-D-aspartate (NMDA) ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/18A61P3/00A61P3/10A61P9/10A61P13/02A61P21/00A61P25/00A61P25/04A61P25/06A61P25/18A61P25/22A61P25/28A61P25/36A61P27/02A61P27/06A61P43/00C07C311/30C07C311/46C07C311/49
CPCC07C2101/14C07C311/49C07C2601/14A61P13/02A61P21/00A61P25/00A61P25/04A61P25/06A61P25/08A61P25/16A61P25/18A61P25/22A61P25/28A61P25/36A61P27/02A61P27/06A61P3/00A61P3/10A61P43/00A61P9/10
Inventor HU, LAIN-YENKESTEN, SUZANNE ROSSLEI, HUANGSHURYDER, TODD ROBERTWUSTROW, DAVID JUERGEN
Owner HU LAIN YEN
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