Anticonvulsant enantiomeric amino acid derivatives

a technology of enantiomeric amino acids and anticonvulsant, which is applied in the direction of biocide, amide active ingredients, organic chemistry, etc., can solve the problems of disturbing side effects, no drug presently available is capable of achieving total seizure control, and a significant percentage of the population with epilepsy or related disorders

Inactive Publication Date: 2004-07-06
RES CORP TECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, despite the many available pharmacotherapeutic agents, a significant percentage of the population with epilepsy or related disorders are poorly managed.
Moreover, none of the drugs presently available are capable of achieving total seizure control, and most have disturbing side effects.
Because many drugs which require chronic administration ultimately place an extra burden on the liver, including for example, liver enzyme induction or oxidative metabolism that may generate reactive species, many anticonvulsants have associated therewith liver toxicity.
Thus, an anti-convulsant agent which has a high anti-convulsant activity, has minimal neurological toxicity and maximal P.I. (protective index) may unfortunately exhibit such toxicities which appear upon repeated high levels of administration.

Method used

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  • Anticonvulsant enantiomeric amino acid derivatives
  • Anticonvulsant enantiomeric amino acid derivatives
  • Anticonvulsant enantiomeric amino acid derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 1

(R)-N-Benzyl-2-Acetamide-3-methoxypropionamide

Hydrochloric acid (8.00 g, 219.4 mmol) was passed into MeOH (250 mL) and then D-Serine (20.00 g, 190.3 mmol) was added. The reaction solution was heated at reflux (18 hours), benzylamine (81.6 mL, 761 mmol) was added and then the reaction was heated for an additional eighteen hours. The solvent was removed under reduced pressure, the insoluble salts filtered, and the excess benzylamine was removed under high vacuum (Kugelrohr). The residue was dissolved in water (100 mL), and the product was extracted with CHCl.sub.3 (8.times.200 mL). The organic layers were combined, dried (Na.sub.2 SO.sub.4), and the solvent was removed under reduced pressure. The residue was triturated with Et.sub.2 O (150 mL) and filtered to give 10.0 g (27%) of the product R-enriched N-benzyl 2-aminohydracrylamide, as a white solid: mp 74.degree.-78.degree. C.; [.alpha.].sub.D.sup.23 (c=1, MeOH)=1.6.degree., R.sub.f 0.30 (10% MeOH--CHCl.sub.3); .sup.1 H NMR (DMSO-d....

example 2

Another Synthesis of (R)-N-Benzyl 2-Acetamide-3-methoxy propionamide

(a) Improved Synthesis of (R)-N-Benzyl 2-Acetamidohydracrylamide

To a stirred AcOH (20 mL) suspension of D-serine (5.26 g, 50 mmol) was added Ac.sub.2 O (4.7 mL, 50 mmol), and then the reaction suspension was stirred at room temperature (24 hours). The ACOH was removed in vacuo to give an oily residue, and then THF (150 mL) was added to the residue. The THF suspension was cooled to -78.degree. C. under N.sub.2 and 4-methylmorpholine (11.0 mL, 100 mmol) was added. After stirring for two minutes, isobutyl chloroformate (13.0 mL, 100 mmol) was added leading to the precipitation of a white solid. The reaction was allowed to proceed for two additional minutes and then benzylamine (10.4 mL, 100 mmol) was added at -78.degree. C. The reaction mixture was allowed to stir at room temperature (30 minutes) and the 4-methylmorpholine hydrochloride salt was filtered. The organic layer was concentrated in vacuo. The product was pur...

example 3

R-N-(3-Fluorobenzyl)2-Acetamide-3-Methoxypropionamide

(a) R-N-(3-Fluorobenzyl)-2-Acetamide-hydracrylamide

Utilizing the procedure of Example 2(a) with the following amounts of D-serine (5.26 g, 50 mmol), Ac.sub.2 O (5.7 mL, 60 mmol), 4-methylmorpholine (11.0 mL, 100 mmol), isobutyl chloroformate (13.0 mL, 100 mmol) and substituting 3-fluorobenzylamine (11.8 mL, 100 mmol) for benzylamine, gave 4.20 g (33%) of the above compound as a white solid after purification: mp 137.degree.-138.degree. C.; [.alpha.].sub.D.sup.23 (c=1, MeOH)=+20.8.degree.; Rf0.32 (10% MeOH--CHCl.sub.3); IR (KBr) 3282, 3101, 2944, 1636, 1542, 1252, 1050, 779, 690 cm.sup.-1 ; .sup.1 H NMR (DMSO-d.sub.6) .delta.1.87 (s,C(O)CH.sub.3), 3.56-3.63 (m, CH.sub.2 OH), 4.29 (d, J=6.0 Hz, CH.sub.2 NH), 4.25-4.30 (m, CH), 4.95 (t, J=5.4 Hz, CH.sub.2 OH), 7.00-7.09 (m, 3 ArH), 7.29-7.30 (m, 1 ArH), 7.97 (d, J=8.1 Hz, NH), 8.44 (t, J=6.0 Hz, NH), addition of excess (R)-(-)-mandelic acid to a CDCl.sub.3 solution of this product ga...

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Abstract

The present invention is directed to a compound in the R configuration about the asymmetric carbon in the following formula: ##STR1## pharmaceutical compositions containing same and the use thereof in treating CNS disorders in animals.

Description

FIELD OF THE INVENTIONThe present invention relates to novel enantiomeric compounds and pharmaceutical compositions useful in the treatment of epilepsy and other CNS disorders.BACKGROUND OF THE INVENTIONThe predominant application of anticonvulsant drugs is the control and prevention of seizures associated with epilepsy or related central nervous system disorders. Epilepsy refers to many types of recurrent seizures produced by paroxysmal excessive neuronal discharges in the brain; the two main generalized seizures are petit mal, which is associated with myoclonic jerks, akinetic seizures, transient loss of consciousness, but without convulsion; and grand mal which manifests in a continuous series of seizures and convulsions with loss of consciousness.The mainstay of treatment for such disorders has been the long-term and consistent administration of anticonvulsant drugs. Most drugs in use are weak acids that, presumably, exert their action on neurons, glial cells or both of the cent...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/165C07C233/05C07C233/00C07C237/06C07C237/52
CPCC07C237/06C07C237/52
Inventor KOHN, HAROLD
Owner RES CORP TECH INC
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