RU99125967A

RU99125967A - SERIOUS PROTEAS INHIBITORS

Info

Publication number: RU99125967A
Application number: RU99125967/04A
Authority: RU
Inventors: Антон Эгберт Петер Аданг
Original assignee: Акцо Нобель Н.В.
Priority date: 1997-05-02
Filing date: 1998-04-28
Publication date: 2001-08-20

Claims

1. The compound of formula I
R ¹ SO ₂ -BXZC (O) -Y
where R ¹ denotes R ² OOC- (CHR ² ) _m - or R ² NH-CO- (CHR ² ) _m -, or is selected from (1-12C) alkyl, (2-12C) alkenyl, which can be optionally substituted (3-12C) cycloalkyl, (1-6C) alkoxy, OH, COOR ² , CF ₃ or halogen, and from (6-14C) aryl, (7-15C) aralkyl and (8-16C) aralkenyl, whose aryl groups may be optionally substituted with (1-6C) alkyl, (3-8C) cycloalkyl, (1-6C) alkoxy, OH, COOH, CF ₃ or halogen;
m is 1, 2 or 3;
each group R ² independently represents H, (1-12C) alkyl, (3-8C) cycloalkyl, (6-14C) aryl or (7-15C) aralkyl, the aryl groups of which may be substituted with (1-6C) alkyl, ( 1-6C) alkoxy or halogen;
B is a bond, an amino acid of the formula —NH — CH [(CH ₂ ) _p C (O) OH] —C (O) - or an ester derivative thereof, where p is 1, 2 or 3, Gly, D-1-Piq , D-3-Piq, D-1-Tiq, D-3-Tiq, D-Atc, Aic or L-or D-amino acid containing a hydrophobic, basic or neutral side chain;
X is an amino acid with a hydrophobic side chain, glutamine, serine, threonine, a cyclic amino acid, optionally containing an additional heteroatom selected from N, O or S, and optionally substituted with (1-6C) alkyl, (1-6C) alkoxy, benzyloxy or oxo or X is 2-amino-isobutyric acid, —NR ² —CH ₂ —C (O) or a group:

or

where n is 2, 3 or 4, W is CH or N, and R ³ is H, (1-6C) alkyl or phenyl, which may be optionally substituted by hydroxyl, (1-6C) alkoxy, COOH, COO (1- 6C) alkyl, CONH ₂ or halogen; Z is lysine or 4-aminocyclohexylglycine; Y is -NH- (1-6C) alkylene-C ₆ H _5, the phenyl group which may be substituted with (1-6C) alkyl, (1-6C) alkoxy or halogen, or Y is -OR ⁴ or -NR ⁵ R ⁶ , where R ⁴ is H, (2-6C) alkyl or benzyl, and R ⁵ and R ^{6 are} independently H, (1-6C) alkoxy or (1-6C) alkyl, optionally substituted with halogen, or R ⁵ and R ⁶ together represent (3-6C) alkylene, or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached represent

where V denotes O, S or SO ₂ ; provided that the following compounds are excluded: naphthyl-SO ₂ -Asp-Pro-Lysψ [COCO] -OH, benzyl-SO ₂ -norLeu (cyclo) Gly-Lysψ [COCO] -OH and ethyl-SO ₂ -D-Phe- Pro-Lysψ [COCO] -OH,
or its prodrug or pharmaceutically acceptable salt.

2. The compound according to claim 1, where Z is lysine.

3. The compound according to claims 1 or 2, where X is a cyclic amino acid, an amino acid with a hydrophobic side chain, glutamine, serine, threonine, -NR ² -CH ₂ -C (O) - or a group

or

where R ³ is H, (1-6C) alkyl or phenyl.

4. The compound according to any one of claims 1 to 3, where X is proline, leucine, glutamine, threonine, phenylalanine, -NR ² -CH ₂ -C (O) -, where R ² denotes methyl, cyclopentyl or cyclohexyl or a group

or

where R ³ denotes H or methyl.

5. The compound according to any one of claims 1 to 4, where B is a bond, a D-amino acid containing a hydrophobic or neutral side chain.

6. The compound according to any one of claims 1 to 5, where R ¹ means (1-6C) alkyl or benzyl.

7. The compound according to any one of claims 1 to 6, where Y denotes-OCH (CH ₃ ) ₂ .

8. The compound according to claim 1, which is [3- (benzylsulfonylamino) -6-methyl-2-oxo-1,2-dihydropyridinyl] -acetyl-Lysψ [COCO] -NH ₂ .
9. A pharmaceutical composition comprising a compound according to any one of claims. 1-8 and pharmaceutically acceptable excipients.

10. The compound according to any one of claims 1 to 8 for use in therapy.

11. The compound according to any one of claims 1 to 8 for obtaining a medicinal product for the treatment or prevention of diseases associated with thrombin.