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1. WO1996040204 - NOVEL INHIBITORS OF COLLAGENASE-1 AND STROMELYSIN-I METALLOPROTEASES, PHARMACEUTICAL COMPOSITIONS COMPRISING SAME AND METHODS OF THEIR USE

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[ EN ]

WHAT IS CLAIMED IS:

1. A compound of the formula:





wherein
A is selected from the group consisting of > C=O and > CHOH; M and Q are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heteroaryl;
R is selected from the group consisting of -NR'R2 and
-NHCH(Q')C(O)NR,R2;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclic and heterocyclicalkyl;
R2 is hydrogen, or R1 and R2 together with the nitrogen atom to which they are attached, form a heterocyclic or heteroaryl ring;
Q' is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, and heteroaryl;

R3 is -(CH2)„-V wherein n is a whole number from 0 to 4 and V is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -OR13, -NR12R13, and -SR13, wherein R12 and R13 are each independently hydrogen, alkyl, substituted alkyl, alkenyl, aryl, arylalkyl, -C(O)-alkyl, -C(O)-substituted alkyl, -C(O)-aryl, -C(O)-heteroaryl, heteroaryl, heterocyclic, heterocyclicalkyl or heteroarylalkyl wherein, in the case of -NR12R13, the nitrogen atom is optionally incorporated into the heteroaryl or heterocyclic ring structure; and
m is an integer from 0 to 2;
or pharmaceutically acceptable salts thereof.

2. The compound according to Claim 1, wherein m is 0 or 1, and M. is alkyl.

3. The compound according to Claim 2, wherein M is heptyl or isobutyl.

4. The compound according to Claim 2, wherein Q is alkyl.

5. The compound according to Claim 4, wherein Q is isobutyl or cyclohexylmethyl.

6. The compound according to Claim 2, wherein R is
-NHCH(Q')C(O)NR1R2 and Q and Q' are each independently alkyl.

7. The compound according to Claim 6, wherein Q is isobutyl or cyclohexylmethyl, and Q is isobutyl.

8. The compound according to Claim 1, wherein m is 0 or 1 and M is substituted alkyl wherein said alkyl substitution is an aryl substitution.

9. The compound according to Claim 8, wherein M is phenylpropyl.

10. The compound according to Claim 8, wherein Q is alkyl.

11. The compound according to Claim 10, wherein Q is isobutyl or cyclohexylmethyl.

12. The compound according to Claim 10, wherein R is
-NHCH(Q')C(O)NR1R2 and Q and Q' are each independently alkyl.

13. The compound according to Claim 12, wherein Q is isobutyl or cyclohexylmethyl, and Q' is isobutyl.

14. A compound according to Claim 1 wherein said compound is selected from the group consisting of
2-wø-butyl-4-oxo-5-mercapto-pentanoyl-(L)-3-cyclohexylalanine- phenethylamide;
2-wø-butyl-3-oxo-4-mercapto-butanoyl]-(L)-j8-cyclohexylalanine- phenethyl-amide;
2-ϊ.rø-butyl-3-hydroxy-4-mercapto-butanoyl-(L)-S-cyclohexylalanine- phenethylamide;

2-wø-butyl-3-oxo-4-mercapto-butanoyl]-(L)-Leu-(L)-Leu-ethylamide;

2-/ι-heptyl-3-hydroxy-4-mercapto-butanoyl-(L)-Leu-(L)-Leu- ethylamide;

2-n-heptyl-3-oxo-4-mercapto-butanoyl-(L)-Leu-(L)-Leu-ethylamide;

2-n-heptyl-3-hydroxy-4-mercapto-butanoyl-(L)-j8-cyclo-hexylalanine- phenethylamide;

2-n-heptyl-3-oxo-4-mercapto-butanoyl-(L)-/3-cyclohexylalanine- phenethylamide;

2-(3-phenylpropyl)-3-hydroxy-4-mercapto-butanoyl-(L)-Leu-(L)-Leu- ethylamide;
2-(3-phenylpropyl)-3-oxo-4-mercapto-butanoyl-(L)-Leu-(L)-Leu- ethy lamide;
2-(3-phenylpropyl)-3-hydroxy-4-mercapto-butanoyl-(L)-j8- cyclohexylalanine-phenethylamide;
2-(3-phenylpropyl)-3-oxo-4-mercapto-butanoyl-(L)-/3- cyclohexylalanine-phenethylamide;
2-/sø-butyl-4-oxo-5-mercapto-pentanoyl-(L)-|3-t-butylglycine- (2-pyridyl)amide;
2-wø-butyl-4-hydroxy-5-mercapto-pentanoyl-(L)-)3-t-butylglycine- (2-pyridyl)amide (including both the D and the L isomers of
the 4 hydroxy substituent);
2-/sø-butyl-4-hydroxy-5-mercapto-pentanoyl-(L)-β-cyclohexyl- alanine-phenethylamide;

2-wø-butyl-3-hydroxy-4-mercapto-butanoyl-(L)-t-butylglycine- methylamide;
2- sø-butyl-3-oxo-4-mercapto-butanoyl-(L)-t-butylglycine- methylamide;
2-z.fø-butyl-4-hydroxy-5-mercapto-pentanoyl-(L)-t-butylglycine- methylamide;
2-n-heptyl-4-hydroxy-5-mercapto-pentanoyl-(L)-Leu-(L)-Leu- ethylamide;

2-n-heptyl-4-oxo-5-mercapto-pentanoyl-(L)-Leu-(L)-Leu- ethylamide;

2-/i-heptyl-3-hydroxy-4-mercapto-butanoyl-(L)-r-butylglycine- methylamide;

2-/ι-heptyl-3-oxo-4-mercapto-butanoyl-(L)-t-butylglycine- methy lamide;

2-n-heptyl-4-hydroxy-5-mercapto-pentanoyl-(L)-r-butylglycine- methylamide;

2-n-heptyl-4-oxo-5-mercapto-pentanoyl-(L)-t-butylglycine- methylamide;

2-n-heptyl-3-hydroxy-4-mercapto-butanoyl-(L)-Leu-phenethylamide;

2-/ι-heptyl-3-oxo-4-mercapto-butanoyl-(L)-Leu-phenethylamide;
2-/ι-heptyl-3-oxo-4-mercapto-butanoyl-(L)-Leu-2-N-morpholino- ethylamide;

2-«-heptyl-3-hydroxy-4-mercapto-butanoyl-(L)-Leu-2-N-morpholino- ethylamide;

2-n-heptyl-3-hydroxy-4-mercapto-butanoyl-(L)-/3-cyclohexylalanine- 2-(4-sulphonamide-phenyl)ethylamide; and
2-«-heptyl-3-hydroxy-4-mercapto-butanoyl-(L)-e-N-tosyl-Lysine-(L)- Leu-ethylamide.

15. A pharmaceutical composition of matter comprising the compound of Claim 1 in an amount effective for treating or controlling disease states associated with collagenase- 1 and/or stromelysin-I
metalloproteases in patients in need of such treatment; and a
pharmaceutically acceptable carrier.

16. A pharmaceutical composition of matter comprising the compound of Claim 1 in an amount effective for treating or controlling disease states or conditions involving tissue breakdown or inflammatory conditions; and a pharmaceutically acceptable carrier.

17. A method for treating or controlling disease states associated with collagenase- 1 and/or stromelysin-I metalloproteases in patients in need of such treatment which method comprises administering to said patient an effective amount of the compound of Claim 1.

18. A method for treating or controlling disease states or conditions involving tissue breakdown or inflammatory conditions comprising administering to a patient in need of such treatment an effective amount of the compound of Claim 1.

19. The compound according to Claim 1 wherein said compound is represented by formula HI.

20. The compound according to Claim 19 wherein V is -OR13 and R13 is hydrogen, alkyl, aryl, or aralkyl.

21. The compound according to Claim 20 wherein V is -NR12R13 and R12 and R13 are each independently hydrogen, alkyl, heteroalkyl, aryl, or aralkyl.

22. The compound according to Claim 20 wherein V is -SR13 and R13 is hydrogen, alkyl, aralkyl, or aryl.

23. The compound according to Claim 22 wherein R3 is