WO1996025387B1 - Alkylcarboxy amino acids-modulators of the kainate receptor - Google Patents

Abstract

Compounds of a class of alkyl carboxy amino acid analogs of glutamic acid according to formula I act as specific regulators of kainic acid EAA receptor cation channel, wherein R1 is 1) CH¿3?, or 2) halogen; R?2 and R3¿ are independently 1) H, 2) C1-C6-alkyl, 3) C3-C4-alkenyl, 4) C3-C5-cycloalkyl, 5) C1-C6-alkyl-CO-, 6) C1-C6-alkyl-OCO-, 7) C1-C6-alkyl-NHCO-, 8) CHO-, or 9) C3-C6-alkynyl; R?2 and R3¿ taken together can be -CH¿2?(CH2)pCH2-; p is 0, 1, 2 or 3; and pharmaceutically acceptable salts of these compounds, but not including compounds of Formula I wherein R?2 and R3¿ are H and R1 is CH¿3 or R?1 is F. These compounds are useful for treating neurological, neuropsychological, neuropsychiatric, neurodegenerative, neuropsychopharmacological and functional disorders associated with excessive or insufficient activation of the kainic acid subtype of the ionotropic EAA receptors; treating cognitive disorders associated with deactivation, suboptimal activation or over-activation of the kainic acid receptor; alleviating pain and improving and enhancing memory, learning, and associated mental processes. A method for designing novel AMPA or kainic acid receptor agonists or antagonists is also disclosed.

Claims

AMENDED CLAIMS[received by the International Bureau on 10 September 1996 (10.09.96); original claims 1 and 4-6 amended; remaining claims unchanged (3 pages)]

1. Alkyl carboxy amino acid compounds having the following formula:

x ^>

wherein: R¹ is

1) CH₃, or

2) halogen;

R² and R³ are independently

1) H,

2) Cl - C6-alkyl,

3) C3 - C4-alkenyl,

4) C3 - C5-cycloalkyl,

5) Cl - C6-alkyl-CO-,

6) Cl - C6-alkyl-OCO-,

7) Cl - C6-alkyl-NHCO-,

8) CHO-, or

9) C3 - C6-alkynyl;

R² and R³ taken together can be -CH₂(CH₂)_PCH₂- ; p is 0, 1, 2 or 3; and pharmaceutically acceptable salts of these compounds, but not including compounds of Formula I where R^: and R³ are H and R¹ is CH₃ or R¹ is F or Cl; or where one of R² or R³ is CHO and the other of R² or R³ is H and R¹ is F. 4 6

2. The compounds of claim 1 of Formula I wherein: R¹ is CH₃;

R² and R³ are independently

1) H,

2) Cl - C3-alkyl,

3) C3 - C4-alkenyl,

4) C3-cycloalkyl,

5) HCO-, or

6) CH₃-(CH₂)_n-CO-;

R² and R³ taken together can be -CH₂(CH₂)_pCH₂-; n is 0 or 1; p is 0, 1, 2 or 3; and pharmaceutically acceptable salts of these compounds; but not including compounds of Formula I where R² and R³ are H and R¹ is CH₃ or R¹ is F.

3. The compounds of claim 2 of Formula I wherein: R² and R³ are independently

1) H,

2) Cl - C3-alkyl,

3) HCO-, or

4) CH₃-CO-; and pharmaceutically acceptable salts of these compounds; but not including compounds of Formula I where R² and R³ are H and R¹ is CH₃ or R¹ is F.

4. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier for administration to a patient in need thereof.

5. The composition of claim 4 wherein the carrier is selected from the group consisting of water, oil, saline, an aqueous sugar solution, and a glycol. 47

6. A pharmaceutical composition comprising a compound selectively modulating ion flow through the Kainate ("KA") receptor in combination with a pharmaceutically acceptable carrier for administration to a patient in need thereof; wherein the compound is an alkyl carboxy amino acid compound having the following formula:

wherein: R¹ is

1) CH₃, or

2) halogen;

R² and R³ are independently

1) H,

2) Cl - C6-alkyl,

3) C3 - C4-alkenyl, . 4) C3 - C5-cycloalkyl,

5) Cl - C6-alkyl-CO-,

6) Cl - C6-alkyl-OCO-,

7) Cl - C6-alkyl-NHCO-,

8) CHO-, or

9) C3 - C6-alkynyl;

R² and R³ taken together can be -CH₂(CH₂)_CH_r ; p is 0, 1 , 2 or 3; and pharmaceutically acceptable salts of these compounds.