RU98117075A

RU98117075A - PROTEASE INHIBITORS SERINE

Info

Publication number: RU98117075A
Application number: RU98117075/04A
Authority: RU
Inventors: Дидерик Ян Гротенхейс Петер; Петрус Антониус Де Ман Адрианус; Эгберт Петер Аданг Антон
Original assignee: Акцо Нобель Н.В.
Priority date: 1996-02-13
Filing date: 1997-02-11
Publication date: 2000-06-10

Claims

1. The compound having the formula I

in which A represents H, optionally substituted D, L-α-hydroxyacetyl, R ¹ , R ¹ -OC (O) -, R ¹ -C (O) -, R ¹ -SO ₂ -, R ² OOC- (CHR ² ) _m -SO ₂ -,
R ² OOC- (CHR ² ) _m -, H ₂ NCO- (CHR ² ) _m - or N-protecting group, where R ^{1 is} selected from the groups (C _1-12 ) alkyl, (C _2-12 ) alkenyl, ( C _2-12 ) alkynyl and (C _3-8 ) cycloalkyl, which may optionally be substituted with (C _3-8 ) cycloalkyl, (C _1-6 ) alkoxy, oxo, OH, COOH, CF ₃ or halogen, and from ( C _6-14 ) aryl, (C _7-15 ) aralkyl and (C _8-16 ) aralkenyl, the aryl groups of which may optionally be substituted with (C _1-6 ) alkyl, (C _3-8 ) cycloalkyl, (C _{1- 6} ) alkoxy, OH, COOH, CF ₃ or halogen; each group R ² independently represents H or has the same meanings as R ¹ ; m is 1, 2 or 3: B is a bond, an amino acid of the formula —NH — CH [(CH ₂ ) _p C (O) OH] —C (O) - or its ester derivatives, p is 0, 1, 2 or 3, N ((C _1-12 ) -alkyl) -CH ₂ -CO-, -N ((C _2-12 ) alkenyl) -CH ₂ -CO-, N ((C _2-12 ) alkynyl) -CH ₂ -CO-, -N- (benzyl) -CH ₂ -CO-, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or L- or a D-amino acid having a hydrophobic, basic or neutral side chain, wherein the amino acid may optionally be substituted with N (C _1-6 ) -alkyl; or A and B together represent the residue R ³ R ⁴ N-CHR ⁵ -C (O) -, in which R ³ and R ⁴ independently represent R ¹ , R ¹ -OC (O) -,
R ¹ -C (O) -, R ¹ -SO ₂ -, R ² OOC- (CHR ² ) _m -SO ₂ -, R ² OOC- (CHR ² ) _m -, H ₂ NCO- (CHR ² ) _m -, or an N-protecting group, or one of R ³ and R ^{4 is} connected to R ⁵ , forming a 5- or 6-membered ring together with the “NC” to which they are attached, and the ring can be condensed with an aliphatic or aromatic 6 -membered ring; and R ⁵ represents a hydrophobic backbone or neutral side chain; X represents an L-amino acid with a hydrophobic side chain representing (C _1-12 ) alkyl optionally substituted with one or more (C _3-8 ) cycloalkyl groups or (C _6-14 ) aryl groups, the hydrophobic side chain optionally being substituted with substituents such as halogen, trifluoromethyl, lower alkyl, lower alkoxy, phenyloxy, benzyloxy, etc., or X is serine, threonine, a cyclic amino acid optionally containing an additional heteroatom selected from N, O or S, and optionally substituted (C _1-6 ) alkyl, (C _1-6 ) alkoc si, benzyloxy or oxo, or X is —NR ² —CH ₂ —C (O) - or a moiety

in which n is 2, 3 or 4, and W represents CH or N; Q is H or —C (O) Y, where Y is H, —CHF ₂ , —CF ₃ , —CO — NH— (C _1-6 ) alkylene-C ₆ H ₅ , —COOR ⁶ wherein R ⁶ is H or ((C _1-6 ) alkyl, -CONR ⁷ R ⁸ where R ⁷ and R ⁸ independently represent H or (C _1-6 ) alkyl, or R ⁷ and R ⁸ together represent (C _3-6 ) alkylene, or Y represents a heterocycle selected from 2-thiazole, 2-thiazoline, 2-benzothiaeol, 2-oxazole, 2-oxazoline and 2-benzoxazole, which heterocycles may optionally be substituted with (C _1-6 ) alkyl, (C _1-6 ) alkoxy or oxo; Z is H or (C _1-6) alkyl, r is 0 or 1 when Q represents -C (O) Y, or equal to 0, 1, 2, 3 or 4 if Q Representat wish to set up H; or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein X is a hydrophobic side chain L-amino acid, serine, threonine, or —NR ² —CH ₂ —C (O) -; and Z is H or methyl.

3. The compound according to claim 1, characterized in that A has the meanings as previously defined; B is a bond, an amino acid of the formula —NH — CH [(CH ₂ ) _p C (O) OH] —C (O) - or its ester derivatives, wherein p is 0, 1, 2 or 3, —N ((C _1-6 ) -alkyl) -CH ₂ -CO-, N - ((C _2-6 ) alkenyl) -CH ₂ -CO-, -N- (benzyl) -CH ₂ -CO-, D-1-Tiq , D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or D-amino acid having a hydrophobic side chain, wherein the amino acid may optionally be N-substituted with (C _1-6 ) alkyl ; or A and B together represent the residue R ³ R ⁴ N-CHR ⁵ -C (O) -; and X is a cyclic amino acid optionally containing an additional heteroatom selected from N, O or S, and optionally substituted with (C _1-6 ) alkyl, (C _1-6 ) alkoxy, benzyloxy or oxo, or X is —NR ² CH ₂ -C (O) - or fragment

and Z is H or methyl.

4. The compound of claim 3, wherein A is H, 2-hydroxy-3-cyclohexylpropionyl-, 9-hydroxyfluoro-9-carboxyl, R ¹ , R ¹ —SO ₂ -, R ² OOC- (CHR ² ) _m -SO ₂ -, R ² OOC- (CHR ² ) _m -, H ₂ NCO- (CHR ² ) _m -, or the P-protecting group, where R ^{1 is} selected from (C _1-12 ) alkyl, (C _1-12 ) alkenyl, (C _6-14 ) aryl, (C _7-15 ) aralkyl and (C _8-16 ) aralkenyl, each group R ² independently represents H or has the same meanings as R ¹ ; B is a bond, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or D-amino acid having a hydrophobic side chain, wherein the amino acid may optionally be substituted N- (C _1-6 ) alkyl; or A and B together represent the residue R ³ R ⁴ N-CHR ⁵ —C (O) -, Y represents —CO — NH— (C _1-6 ) alkylene-C ₆ H ₅ , —COOR ⁶ , —CONR ⁷ R ⁸ or Y represents a heterocycle selected from 2-thiazole, 2-thiazoline, 2-benzothiazole, 2-oxazole, 2-oxazoline and 2-benzoxazole.

5. The compound according to p. 4, characterized in that A represents R ¹ -SO ₂ -, R ² OOC- (CHR ² ) _m -; B represents a bond, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-piq or D-amino acid having a hydrophobic side chain, or A and B together represent a radical R ³ R ⁴ N-CHR ⁵ -C (O) -, where at least one of R ³ and R ⁴ is R ² OOC- (CHR ² ) _m or R ¹ -SO ₂ -, and the other independently represents ( C _1-12 ) alkyl, (C _2-12 ) alkenyl, (C _2-12 ) alkynyl, (C _3-8 ) cycloalkyl, (C _7-15 ) aralkyl or R ¹ -SO ₂ - or R ² OOC ( CHR ² ) _m and R ⁵ represents a hydrophobic side chain; Y is —CO — NH— (C _1-6 ) alkylene-C ₆ H ₅ , —COOR ⁶ , and R ⁶ is H or (C _1-3 ) alkyl, —CONR ⁷ R ⁸ , R ⁷ and R ⁸ independently represent H or (C _1-3 ) alkyl, or R ⁷ and R ⁸ together represent (C _3-5 ) alkylene, or Y represents a heterocycle selected from 2-thiazole, 2-benzothiazole, 2-oxazole or 2-beneoxazole .

6. The compound according to p. 5, characterized in that A represents R ² OOC- (CHR ² ) _m -, B represents a D-amino acid having a hydrophobic side chain; or A and B together represent the remainder R ³ R ⁴ N-CHR ⁵ C (O) -, where at least one of R ³ and R ⁴ represents R ² OOC- (CHR ² ) _m and the other independently represents (C _{1 -12} ) alkyl, (C _3-8 ) cycloalkyl, R ¹ -SO ² - or R ² OOC- (CHR ² ) _m -, and X is 2-azetidine carboxylic acid, proline, pipecolic acid, 4-thiazolidine carboxylic acid, 3 , 4-dehydroproline, 2-octahydroindolecarboxylic acid.

7. The compound of claim 6, wherein A is HOOC-CH ₂ ; B represents D-Phe, D-Cha, D-Coa, D-Dpa, p-Cl-D-Phe, p-OMe-D-Phe, p-OEt-D-Phe, D-Nle, m-Cl- D-Phe, 3,4-di-OMe-D-Phe, D-Chg; or A and B together represent the residue R ³ R ⁴ N-CHR ⁵ -C (O) -, where at least one of R ³ and R ⁴ is HOOC-CH ₂ - and the other independently is methyl, (C _1-4 ) alkyl-SO ₂ - or HOOC-CH ₂ , and R ⁵ is (C _3-8 ) cycloalkyl, (C _3-8 ) cycloalkyl- (C _1-4 ) alkyl, phenyl, benzyl optionally substituted with chlorine or (C _1-4 ) alkoxy.

8. The compound according to claim 5, characterized in that A represents R ¹ -SO ₂ -, B represents a bond, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D- 3-Piq or D-amino acid having a hydrophobic side chain; or A and B together represent the residue R ³ R ⁴ N-CHR ⁵ -C (O) -, where at least one of R ³ and R ⁴ is R ¹ -SO ₂ - and the other independently represents (C _1-12 ) alkyl or R ¹ —SO ₂ -; X represents 2-azetidine carboxylic acid, proline, pipecolic acid, 4-thiazolidine carboxylic acid, 3,4-dehydroproline, 2-octahydroindole carboxylic acid, or a fragment

9. The compound according to p. 8, characterized in that A represents ethyl-SO ₂ - or benzyl-SO ₂ -; B represents a bond, D-Phe, D-Cha, D-Coa, D-Dpa, -Cl-D-Phq, -OMe-D-Phe, -OEt-D-Phe, D-Nle, M-Cl-D -Phe, 3,4-di-OMe-D-Phe, D-Chg; or A and B together represent the residue R ³ R ⁴ NC (O) -, where at least one of R ³ and R ⁴ represents ethyl-SO ₂ - or benzyl-SO ₂ -, and the other independently represents (C _1-12 ) alkyl or R ¹ -SO ₂ -, and R ⁵ represents (C _3-8 ) cycloalkyl, (C _3-8 ) -cycloalkyl- (C _1-4 ) alkyl, phenyl, benzyl, diphenylmethyl, with the groups optionally substituted with chlorine or (C _1-4 ) alkoxy.

10. The compound according to any one of claims 5 to 9, characterized in that Q is H and r is 0, 1 or 2.

11. A pharmaceutical composition comprising a compound according to any one of paragraphs. 1-10 and pharmaceutically acceptable excipients.

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

13. The use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment or prevention of diseases associated with thrombin.