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Sydnonimines-specific dopamine reuptake inhibitors and their use in treating dopamine related disorders

a dopamine-related disorder and reuptake inhibitor technology, applied in the field of sydnonimine derivatives, can solve the problems of no long-term efficacy, no long-term efficacy, increased activity or resistance to participate or respond, etc., and achieves no propensity for conversion, suppress locomotor activity

Inactive Publication Date: 2009-08-27
CHEN HAO +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because cocaine interacts with a number of neurotransport processes in the brain, as noted above, the discovery of a medication that is capable of antagonizing the effect of cocaine in clinical trials, without producing sedative or other undesirable side effects has proven to be a formidable task, and to date not successfully accomplished.
Indeed, a number of clinically available medications approved for other therapeutic indications, especially reuptake / transporter blockers and / or receptor agonists, have been or are being tested in clinical trials for effectiveness in curtailing cocaine craving, dependency, and addiction; however, none has yet demonstrated long term efficacy.
Inappropriate inattention causes increased rates of activity or reluctance to participate or respond.
Additionally, these mice were impaired in spatial cognitive function, and they showed a decrease in locomotion in response to psychostimulants.
One of the principal impediments to the success of treatments for schizophrenia is that patients frequently discontinue prescribed medication(s), especially those having undesirable side effects, such as blurred vision, dizziness, muscle spasms, cramps, tremors and other Parkinson-like symptoms.

Method used

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  • Sydnonimines-specific dopamine reuptake inhibitors and their use in treating dopamine related disorders
  • Sydnonimines-specific dopamine reuptake inhibitors and their use in treating dopamine related disorders
  • Sydnonimines-specific dopamine reuptake inhibitors and their use in treating dopamine related disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of N-phenylcarbamoyl-3-(benzyl)-sydonimine

[0092]1.2 ml 7.5N aq. HCl was stirred (at 0° C.) into a mixture of 0.94 g benzyl amine and 0.58 g of potassium cyanide in 2 ml of water. 0.7 g formaldehyde was then added dropwise into the mixture. The resulting mixture was stirred at room temperature for 2 hours and then cooled to 0° C. A solution of 0.62 g sodium nitrite in 1 ml water was added slowly dropwise to the mixture followed by the addition of 1.2 ml 7.5N HCl aq. solution while cooling. The mixture was stirred at room temperature for 1 hour. Ether was used to extract the resulting mixture three times. The combined ether solution was dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure. N-nitroso-benzylaminoacetonitrile (see reaction scheme) was obtained as a yellow oil. The nitroso intermediate was then treated with 500 ml HCl ethereal solution (2.0 M) and stirred for 30 minutes at room temperature. White precipitate was obtained and recr...

examples 2-7

[0093]The compounds N-phenylcarbamoyl-3-(p-carboxylbenzyl-syndonimine (2); N-phenylcarbamoyl-3-(p-methyl-benzyl)-sydnonimine (3); N-(3′,4′-dichlorophenyl) carbamoyl-3-phenethyl sydnonimine (4); N-(3′,4′-dinitrophenyl) carbamoyl-3-p-nitrophenethyl sydnonimine (5); N-phenylcarbamoyl-3-(phenylpropyl)-sydnonimine (6); and N-phenylcarbamoyl-3-p-fluoro-benzyl)-sydnonimine (7) were synthesized following essentially the same procedure as described in Example 1, above, with appropriate substitution of different starting materials in equivalent amounts.

example 8

I. Dopamine Transporter Binding Assay [3H]WIN 35,428

[0094]This assay was carried out according to the procedure described by Javitch, J. J. et al., Mol. Pharmacol. 26: 35-44; 1984

[0095]A. Tissue Preparation (Prepare All Solutions On Ice)[0096]1. Thaw frozen brains from male Guinea Pigs (in assay buffer) and place in 50 mM TRIS-HCl (pH 7.4 at 25° C. with 120 mM NaCl). Isolate striatum.[0097]2. Use a Polytron to homogenize tissue in 20 vols. (w / v) of 50 mM Tris-HCl (pH 7.4 at 25° C. with 120 mM NaCl).[0098]3. Centrifuge homogenate at 48,400×g for approximately 10 minutes at 4° C. Discard supernatant.[0099]4. Wash pellet an additional time as described in steps 2 and 3.[0100]5. Store pellet on ice until needed for binding assay.[0101]6. Using a Polytron (setting 5; approximately 10 seconds) resuspend pellet in 50 mM Tris-HCl (pH 7.4 at 25° C. with 120 mM NaCl) to an initial concentration of 10 mg / ml (original wet weight), such that the final concentration is 8 mg / ml or 4.0 mg tissue / t...

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Abstract

Derivatives of Sydnonimine and its analogues, which bind selectively to dopamine transporter (DAT) proteins are useful for treating and delaying the progression of disorders and illnesses that are alleviated by inhibiting dopamine reuptake.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application claims the benefit of U.S. Provisional Patent Application No. 60 / 894,739, filed Mar. 14, 2007, the entire disclosure of which is incorporated by reference herein.GOVERNMENT RIGHTS STATEMENT[0002]The invention described herein was made with funding provided by the U.S. National Institutes of Health, under Grant Nos. IR43DA013353-01, 2R44DA013353-02A1, 5R44DA013353-03, 2R44DA013353-04A1, 5R44DA013353-05 and 5R44DA013353-06. The Government has certain rights in this invention.FIELD OF THE INVENTION[0003]The present invention relates to certain Sydnonimine derivatives that bind specifically to dopamine transporter (DAT) proteins or the site of dopamine reuptake, compositions comprising same, and the use of such derivatives for treating, or delaying the progression of, various disorders and illnesses alleviated by inhibiting dopamine reuptake.BACKGROUND OF THE INVENTION[0004]Neurotransmitters are chemical “messengers” t...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4245
CPCC07D271/04A61K31/4245A61P3/04A61P9/00A61P11/00A61P15/08A61P15/10A61P25/00A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/30A61P25/32A61P25/36A61P27/02A61P29/00A61P35/00A61P37/06A61P43/00
Inventor CHEN, HAOLIU, MINGSU, QIRAISINGHANI, MANISH
Owner CHEN HAO
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