3-Alkoxyisoxazol-4-yl-substituted 2-amino carboxylic acid compounds

• US 6,200,999 B1
• Filed: 05/20/1999
• Issued: 03/13/2001
• Est. Priority Date: 10/04/1996
• Status: Expired due to Fees

• Current Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Original Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Inventors: Krogsgaard-Larsen, Povl, Bang-Andersen, Benny, Bøgesø, Klaus Peter, Moltzen Lenz, Sibylle
• Primary Examiner(s): Stockton, Laura L.
• Application Number:
  US09/269,356
• Time in Patent Office: 663 Days
• Field of Search: 548/243, 514/380
• US Class Current: 514/380
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 261/12 Oxygen atoms
• CPC Class Codes: C07D 261/18 Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 275/03 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Abstract

(3-Alkoxyisoxazol-4-yl)-substituted 2-amino carboxylic acid derivatives and sulfur analogues thereof having general formula (I) or (II),

wherein R₁ is hydrogen, alkyl, alkenyl, alkynyl, cycloalk(en)yl, cycloalk(en)yl-alk(en/yn)yl or optionally substituted phenyl-alk(en/yn)yl; A is a bond or a hydrocarbon spacer group; B is a group —CR_a(NR_bR_c)—COOR₅ wherein R_a-R_c are independently hydrogen or alkyl, and R₅ is defined as R₁ or pivaloyloxymethyl, or B is a group of Formula (III),

wherein R₂, R₃ and R₄ are independently selected from hydrogen, a non-aromatic hydrocarbon group, phenyl- and thienyl-alkyl, and a hetero aliphatic group, or R₃ and R₄ are connected, thereby forming an alkylene, alkenylene or alkynylene group, or R₄ and R₂ are connected in order to form an alkylene, alkenylene or alkynylene group, optionally substituted with hydroxy or methyl, or to form CH₂—O—CH₂; E is COOR₆, where R₆ is defined as R₅, or E is a tetrazolyl or triazolyl; X is O or S; and Y is O or S; are excitatory amino acid (EAA), in particular AMPA and/or NMDA receptor ligands, useful in the treatment of cerebral ischaemia, Huntington'"'"'s disease, epileptic disorders, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, schizophrenia, pain, depression and anxiety.

Claims

1. A (3-alkoxyisoxazol-4-yl)-substituted 2-amino carboxylic acid derivative having general Formula I or II

wherein R₁ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, cycloalk(en)yl, cycloalk(en)yl-C_1-6alk(en/yn)yl or phenyl-C_1-6alk(en/yn)yl, the phenyl group being optionally substituted with CF₃, halogen, C_1-6 alkyl or C_1-6 alkoxy;

A is a bond or a spacer group selected from C_1-6 alkylene, C_2-6 alkenylene, C_2-6 alkynylene, and cycloalkylene;

B is a group —

CR_a (NR_bR_c)—

COOR₅ wherein R_a-R_c are independently hydrogen or C_1-6 alkyl, and R₅ is defined as R₁ or pivaloyloxymethyl, or B is a group of Formula III

 

wherein R₂, R₃ and R₄ are independently selected from the group consisting of

a) hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, cycloalk(en)yl, cycloalk(en)yl-C_1-6 alk(en/yn)yl, phenyl-C_1-6 alkyl, thienyl-C_1-6-alkyl, and

b) C_1-6 alkyl, C_2-6 alkenyl and C_2-6 alkynyl in which one or more carbon atoms are replaced by N, O, and/or S, or

R₃ and R₄ are connected, thereby forming a C₂-C₆ alkylene, C₂-C₆ alkenylene or C₂-C₆ alkynylene group, or

R₄ and R₂ are connected in order to form a C₁-C₃ alkylene, C₂-C₃ alkenylene or C₂-C₃ alkynylene group optionally mono- or di-substituted with hydroxy or methyl, or to form CH₂—

O—

CH₂;

E is COOR₆, where R₆ is defined as R₅;

X is O;

Y is O or S;

or a

pharmaceutically acceptable salt thereof.

2. A compound of claim 1 which has Formula I.

3. A compound of claim 1 which has Formula II.

4. A compound of claim 1, wherein R₆ is not hydrogen.

5. A compound of claim 1, wherein E is COOH.

6. A compound of claim 1, wherein B is a group of the formula CR_a(NR_bR_c)—

COOR₅.

7. A compound of claim 6, wherein R_b and R_c are hydrogen and R_a is hydrogen or C_1-6 alkyl.

8. A compound of claim 1, wherein R₅ is hydrogen.

9. A compound of claim 1, wherein R₅ is not hydrogen.

10. A compound of claim 1, wherein B is a group of the formula III.

11. A compound of claim 10, wherein R₂, R₃ and R₄ are hydrogen or C_1-6 alkyl, or R₄ and R₂ are connected in order to form a C₁-C₃ alkylene group.

12. A compound of claim 11, wherein each of R₂, R₃ and R₄ are hydrogen.

13. A compound of claim 1, wherein Y is oxygen.

14. A compound of claim 1, wherein Y is sulfur.

15. A compound of claim 1, wherein R₁ is C_1-6 alkyl, C_2-6 alkenyl or C_2-6 alkynyl.

16. A compound of claim 1, wherein A is a bond or C₁-C₃ alkylene.

17. A compound of claim 2, wherein A is a bond or C₁-C₃ alkylene, B is —

CH(NH₂)—

COOH or a group of Formula III wherein each of R₃, R₄ and R₂ are hydrogen, Y is oxygen, and R₁ is C_1-6 alkyl, C_2-6 alkenyl or C_2-6 alkynyl.

18. A compound of claim 1 wherein R₆ is selected from the group consisting of C_1-6 alkyl phenyl-C_1-6, alk(en/yn)yl and pivaloyloxymethyl.

19. A compound of claim 15 wherein R₁ is selected from the group consisting of methyl, ethyl, propyl or propargyl.

20. A compound of claim 16 wherein said C_1-3 alkylene is methylene.

21. A compound of claim 17 wherein R₁ is selected from the group consisting of methyl, ethyl, propyl or propargyl.

22. A pharmaceutical composition comprising a compound of claim 1 together with a pharmaceutically acceptable carrier or diluent.

23. A method of treating cerebral ischaemia, Huntington'"'"'s disease, epileptic disorders, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, schizophrenia, pain, depression or anxiety, said method comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.