Inhibitors of TNF-.alpha. secretion

• US 5,629,285 A
• Filed: 05/22/1996
• Issued: 05/13/1997
• Est. Priority Date: 08/23/1993
• Status: Expired due to Term

• Current Assignee: Immunex Corporation (Amgen Inc.)
• Original Assignee: Immunex Corporation (Amgen Inc.)
• Inventors: Black, Roy A., Sleath, Paul R., Fitzner, Jeffrey N.
• Primary Examiner(s): CONRAD III, JOSEPH M
• Application Number:
  US08/651,363
• Time in Patent Office: 356 Days
• Field of Search: 514/7, 514/2, 514/507, 514/563, 514/119
• US Class Current: 514/20.1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07C 259/06 having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07K 5/0202 containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
• CPC Class Codes: C07K 5/06034 the side chain containing 2 to 4 carbon atoms
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/06086 with the first amino acid being basic
• CPC Class Codes: C07K 5/06095 Arg-amino acid

Abstract

Compounds and methods are disclosed that are useful in inhibiting the TNF-α converting enzyme (TACE) responsible for cleavage of TNF-α precursor to provide biologically active TNF-α. The compounds employed in the invention are peptidyl derivatives having active groups capable of inhibiting TACE such as, hydroxamates, thiols, phosphoryls and carboxyls.

Claims

1. A method for treating a mammal having a disease characterized by an overproduction or an unregulated production of TNF-α

, comprising administering to the mammal a composition comprising an effective amount of a biologically active compound of the formula;

wherein;

X is hydroxamic acid, phosphoryl or carboxyl;

m is 0, 1 or 2;

R¹, R² and R³ each independent of the other is hydrogen, alkylene(cycloalkyl), OR⁴, SR⁴, N(R⁴)(R⁵), halogen, substituted or unsubstituted C₁ to C₈ alkyl, C₁ to C₈ alkylenearyl, aryl, a protected or unprotected side chain of a naturally occurring α

-amino acid;

or the group --R⁶ R⁷, wherein R⁶ is C₁ to C₈ alkyl and R⁷ is OR⁴, SR⁴, N(R⁴)(R⁵) or halogen, wherein R⁴ and R⁵ are each, independent of the other, hydrogen or substituted or unsubstituted C₁ to C₈ alkyl;

n is 1 or 2;

Y is hydrogen, unsubstituted or substituted C₁ to C₈ alkyl, alkylene(cycloalkyl), the group --R⁸ --COOR⁹ or the group --R¹⁰ N(R¹¹)(R¹²);

wherein R⁸ is C₁ to C₈ alkylene;

R⁹ is hydrogen or C₁ to C₈ alkyl;

R¹⁰ is C₁ to C₈ alkylene; and

R¹¹ and R¹² are each, independent of the other, hydrogen or unsubstituted or substituted C₁ to C₈ alkyl;

provided that when n is 1, A is a protected or an unprotected α

-amino acid radical; and

when n is 2, A is the same or different protected or unprotected α

-amino acid radical; and

when n is 2, A is the same or different protected or unprotected α

-amino acid radical; and

the pharmaceutically acceptable salts thereof;

wherein the compound is capable of reducing serum TNF-α

levels by at least 80% when administered at 25 mg/kg in a murine model of LPS-induced sepsis syndrome;

and a pharmaceutically acceptable carrier.

2. The method according to claim 1, wherein B is C₂ to C₆ alkylene.

3. The method according to claim 2, wherein B is dimethylene.

4. The method according to claim 1, wherein X is hydroxamic acid.

5. The method according to claim 1, wherein R¹ is hydrogen or C₁ to C₆ alkyl.

6. The method according to claim 5, wherein R¹ is hydrogen.

7. The method according to claim 1, wherein R² is hydrogen or C₁ to C₆ alkyl.

8. The method according to claim 7, wherein R² is isobutyl.

9. The method according to claim 1, wherein R³ is selected from the group consisting of C₁ to C₆ alkyl, C₁ to C₆ alkylenephenol, C₁ to C₆ alkylene(cycloalkyl) or C₁ to C₆ alkylenearyl.

10. The method according to claim 9, wherein R³ is C₁ to C₆ alkyl.

11. The method according to claim 10, wherein R³ is t-butyl.

12. The method according to claim 9, wherein R³ is C₁ to C₆ alkylenearyl.

13. The method according to claim 12, wherein R³ is methylene-(2'"'"'-naphthyl).

14. The method according to claim 1, wherein A is an alanyl or seryl radical, and n is 1.

15. The method according to claim 14, wherein A is alanyl, and n is 0 or 1.

16. The method according to claim 1, wherein the compound is N-{D,L-2-(hydroxyaminocarbonyl)methyl-4-methylpentanoyl}-L-3-(2'"'"'-naphthyl)alanyl-L-alanine, 2-(amino)ethyl amide.

17. The method according to claim 1, wherein the compound is N-{D,L-2-(hydroxyaminocarbonyl)methyl-4-methylpentanoyl}-L-3-amino-2-dimethylbutanoyl-L-alanine, 2-(amino)ethyl amide.

18. A pharmaceutical composition for treating TNF-α

related disorders, conditions or diseases, comprising an effective amount of a biologically active compound of the formula;

##STR16## wherein;

X is hydroxamic acid, phosphoryl or carboxyl;

m is 0, 1 or 2;

R¹, R² and R³ each independent of the other is hydrogen, alkylene(cycloalkyl), OR⁴, SR⁴, N(R⁴)(R⁵), halogen, substituted or unsubstituted C₁ to C₈ alkyl, C₁ to C₈ alkylenearyl, aryl, a protected or unprotected side chain of a naturally occurring α

-amino acid;

or the group --R⁶ R⁷, wherein R⁶ is substituted or unsubstituted C₁ to C₈ alkyl and R⁷ is OR⁴, SR⁴, N(R⁴)(R⁵) or halogen, wherein R⁴ and R⁵ are each, independent of the other, hydrogen or substituted or unsubstituted C₁ to C₈ alkyl;

n is 1 or 2;

provided that when n is 1, A is a protected or an unprotected α

-amino acid radical;

when n is 2, A is the same or different protected or unprotected α

-amino acid radical;

B is unsubstituted or substituted C2 to C8 alkylene; and

the pharmaceutically acceptable salts thereof.

19. A pharmaceutical composition according to claim 18 further comprising a protein having TNF-α

binding activity.