Treatment of global and focal ischemia using naaladase inhibitors

• US 5,824,662 A
• Filed: 09/27/1996
• Issued: 10/20/1998
• Est. Priority Date: 09/27/1996
• Status: Expired due to Term

• Current Assignee: Eisai Incorporated (Eisai Medical Research Incorporated)
• Original Assignee: Guilford Pharmaceuticals Inc. (M G I Pharma Incorporated)
• Inventors: Slusher, Barbara S., Jackson, Paul F.
• Primary Examiner(s): MACMILLAN, KEITH D
• Application Number:
  US08/718,703
• Time in Patent Office: 753 Days
• Field of Search: 514/574, 514/921, 514/75
• US Class Current: 514/75
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• CPC Class Codes: A61K 31/661 Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• CPC Class Codes: A61K 31/662 Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• CPC Class Codes: A61K 31/665 having oxygen as a ring hetero atom, e.g. fosfomycin
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: C07F 9/301 Acyclic saturated acids which can have further substituents on alkyl

Abstract

The present invention includes compositions and methods of treatment for glutamate abnormalities and associated nervous tissue insult in a animal by inhibition of NAALADase enzyme. Compositions include glutamate-derived hydroxyphosphinyl derivative compounds, acidic peptide analogs, phosphinic acid derivatives and mixtures thereof that inhibit NAALADase enzyme activity and their use for treating glutamate abnormalities such as created by global and focal ischemia.

Claims

1. A method for treating glutamate abnormalities which comprises administering an effective amount of a NAALADase inhibitor to an animal, wherein the NAALADase inhibitor is a compound having the formula:

##STR8## where R is hydroxy, C₁ -C₉ straight or branched chain alkyl or alkenyl group, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl, or Ar₁,

wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar₁ group is optionally substituted with C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl, C₁ -C₄ alkyl, C₁ -C₄ alkenyl, hydroxy, halo, nitro, trifluoromethyl, C₁ -C₆ straight or branched chain alkyl or alkenyl, C₁ -C₄ alkoxy, C₁ -C₄ alkenyloxy, phenoxy, benzyloxy, amino, or Ar₁, and where Ar₁ is selected from the group consisting of naphthyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C₁ -C₆ straight or branched alkyl or alkenyl, C₁ -C₄ alkoxy or C₁ -C₄ alkenyloxy, phenoxy, benzyloxy, and amino;

or a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

6. The method of claim 1, wherein the effective amount of a NAALADase inhibitor is administered in combination with an additional therapeutic agent.

2. A method for treating glutamate abnormalities which comprises administering an effective amount of a NAALADase inhibitor to an animal, wherein the NAALADase inhibitor is selected from the group consisting of:

2- methylhydroxyphosphinyl!methyl!pentanedioic acid;

2- ethylhydroxyphosphinyl!methyl!pentanedioic acid;

2- propylhydroxyphosphinyl!methyl!pentanedioic acid;

2- butylhydroxyphosphinyl!methyl!pentanedioic acid;

2- cyclohexylhydroxyphosphinyl!methyl!pentanedioic acid;

2- phenylhydroxyphosphinyl!methyl!pentanedioic acid;

2- 2-(tetrahydrofuranyl)hydroxyphosphinyl!methyl!pentanedioic acid;

2- (2-tetrahydropyranyl)hydroxyphosphinyl!methyl!pentanedioic acid;

2- ((4-pyridyl)methyl)hydroxyphosphinyl!methyl!pentanedioicacid;

2- ((2-pyridyl)methyl)hydroxyphosphinyl!methyl!pentanedioicacid;

2- (phenylmethyl)hydroxyphosphinyl!methyl!pentanedioic acid;

2- ((2-phenylethyl)methyl)hydroxyphosphinyl!methyl!pentanedioic acid;

2- ((3-phenylpropyl)methyl)hydroxyphosphinyl!methyl!pentanedioic acid;

2- ((3-phenylbutyl)methyl)hydroxyphosphinyl!methyl!pentanedioic acid;

2- ((2-phenylbutyl)methyl)hydroxyphosphinyl!methyl!pentanedioic acid;

2- (4-phenylbutyl)hydroxyphosphinyl!methyl!pentanedioic acid; and

2- (aminomethyl)hydroxyphosphinyl!methyl!pentanedioic acid.

3. A method for treating glutamate abnormalities which comprises administering an effective amount of a NAALADase inhibitor to an animal, wherein the NAALADase inhibitor is selected from the group consisting of:

2- methylhydroxyphosphinyl!methyl!pentanedioic acid;

2- ethylhydroxyphosphinyl!methyl!pentanedioic acid;

2- propylhydroxyphosphinyl!methyl!pentanedioic acid; and

2- phenylhydroxyphosphinyl!methyl!pentanedioic acid.

4. A method for treating glutamate abnormalities which comprises administering an effective amount of a NAALADase inhibitor to an animal, wherein the NAALADase inhibitor is selected from the group consisting of:

2-(phosphonomethyl)pentanedioic acid;

2-(phosphonomethyl)succinic acid; and

,

2- (2-carboxyethyl)hydroxyphosphinyl!methyl!pentanedioic acid.

5. A method for treating glutamate abnormalities which comprises administering an effective amount of a NAALADase inhibitor to an animal, wherein the NAALADase inhibitor is 2-(phosphonomethyl)pentanedioic acid.

7. A method for treating ischemia which comprises:

administering an effective amount of a NAALADase inhibitor to an animal suffering from ischemia, wherein the NAALADase inhibitor is a compound having the formula;

##STR9## where R is hydroxy, C₁ -C₉ straight or branched chain alkyl or alkenyl group, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl, or Ar₁,

wherein said alkyl, alkenyl cycloalkyl, cycloalkenyl or Ar₁ group is optionally substituted with C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl, C₁ -C₄ alkyl, C₁ -C₄ alkenyl, hydroxy, halo, nitro, trifluoromethyl, C₁ -C₆ straight or branched chain alkyl or alkenyl, C₁ -C₄ alkoxy, C₁ -C₄ alkenyloxy, phenoxy, benzyloxy, amino, or Ar₁, and where Ar₁ is selected from the group consisting of napthyl, indolyl, furyl, thienyl, pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C₁ -C₆ straight or branched alkyl or alkenyl, C₁ -C₄ alkoxy or C₁ -C₄ alkenyloxy, phenoxy, benzyloxy, and amino;

or a pharmaceutically acceptable salt, hydrate, or a mixture thereof.

12. The method of claim 7, wherein the effective amount of a NAALADase inhibitor is administered in combination with an additional therapeutic agent.

8. A method for treating ischemia which comprises:

administering an effective amount of a NAALADase inhibitor to an animal suffering from ischemia, wherein the NAALADase inhibitor is selected from the group consisting of;

2- methylhydroxyphosphinyl!methyl!pentanedioic acid;

2- ethylhydroxyphosphinyl!methyl!pentanedioic acid;

2- propylhydroxyphosphinyl!methyl!pentanedioic acid;

2- butylhydroxyphosphinyl!methyl!pentanedioic acid;

2- cyclohexylhydroxyphosphinyl!methyl!pentanedioic acid;

2- phenylhydroxyphosphinyl!methyl!pentanedioic acid;

2- 2-(tetrahydrofuranyl)hydroxyphosphinyl!methyl!pentanedioic acid;

2- (2-tetrahydropyranyl)hydroxyphosphinyl!methyl!pentanedioic acid;

2- ((4-pyridyl)methyl)hydroxyphosphinyl!methyl!pentanedioicacid;

2- ((2-pyridyl)methyl)hydroxyphosphinyl!methyl!pentanedioicacid;

2- (phenylmethyl)hydroxyphosphinyl!methyl!pentanedioic acid;

2- ((2-phenylethyl)methyl)hydroxyphosphinyl!methyl!pentanedioic acid;

2- ((3-phenylpropyl)methyl)hydroxyphosphinyl!methyl!pentanedioic acid;

2- ((3-phenylbutyl)methyl)hydroxyphosphinyl!methyl!pentanedioic acid;

2- ((2-phenylbutyl)methyl)hydroxyphosphinyl!methyl!pentanedioic acid;

2- (4-phenylbutyl)hydroxyphosphinyl!methyl!pentanedioic acid; and

2- (aminomethyl)hydroxyphosphinyl!methyl!pentanedioic acid.

9. A method for treating ischemia which comprises:

administering an effective amount of a NAALADase inhibitor to an animal suffering from ischemia, wherein the NAALADase inhibitor is selected from the group consisting of;

2- methylhydroxyphosphinyl!methyl!pentanedioic acid;

2- ethylhydroxyphosphinyl!methyl!pentanedioic acid;

2- propylhydroxyphosphinyl!methyl!pentanedioic acid; and

2- phenylhydroxyphosphinyl!methyl!pentanedioic acid.

10. A method for treating ischemia which comprises:

administering an effective amount of a NAALADase inhibitor to an animal suffering from ischemia, wherein the NAALADase inhibitor is selected from the group consisting of;

2-(phosphonomethyl)pentanedioic acid;

2-(phosphonomethyl)succinic acid; and

,

2- (2-carboxyethyl)hydroxyphosphinyl!methyl!pentanedioic acid.

11. A method for treating ischemia which comprises:

administering an effective amount of a NAALADase inhibitor to an animal suffering from ischemia, wherein the NAALADase inhibitor is 2-(phosphonomethyl)pentanedioic acid.