Modulators of SREBP processing

• US 6,649,593 B1
• Filed: 10/06/2000
• Issued: 11/18/2003
• Est. Priority Date: 10/13/1999
• Status: Expired due to Fees

• Current Assignee: Amgen Inc., Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Tularik, Inc. (Amgen Inc.), Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Jaen, Juan C., Cheng, Dong, Brown, Michael S., Goldstein, Joseph L., Li, Leping
• Primary Examiner(s): Weber, Jon P.
• Application Number:
  US09/680,571
• Time in Patent Office: 1,138 Days
• Field of Search: 514/15, 514/16, 514/17, 514/18, 514/19, 530/328, 530/329, 530/330, 530/331
• 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: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: C07K 5/0815 with the first amino acid being basic
• CPC Class Codes: C07K 5/0817 the first amino acid being Arg
• CPC Class Codes: C07K 5/1019 with the first amino acid being basic

Abstract

Compounds, compositions and methods are provided for the inhibition of S1 protease and for the modulation of cholesterol homeostasis in a cell.

Claims

1. A compound of the formula:

2. A compound in accordance with claim 1, wherein

X is NH or N(C₁-C₄)alkyl;

and

n′

is 0 or 1.

3. A compound in accordance with claim 1, wherein

R¹ is a member selected from the group consisting of (C₁-C₃)alkyl, aryl(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and aryl(C₁-C₃)alkoxy;

R² is selected from the group consisting of;

wherein

X is NH;

n′

is 0 or 1;

R¹¹, R¹⁴ and R¹⁵ are each H;

R¹² is selected from the group consisting of (C₁-C₄)alkyl, (C₂-C₈)heteroalkyl and aryl(C₁-C₂)alkyl; and

R¹³ is selected from the group consisting of H, CH₂Cl, CF₃, heteroaryl, CO₂R¹⁶ and CONHR¹⁶.

4. A compound in accordance with claim 1, wherein R² is a radical of the formula:

wherein

X is NH, n′

is O, R¹¹ is H, R¹² is a member selected from the group consisting of 2-methyl-1-propyl, methyl, benzyl, 4-amino-1-butyl and 3-guanidino-1-propyl, and R¹³ is a member selected from the group consisting of H, CH₂Cl, CF₃, CONHEt, CO₂Et and 2-thiazolyl.

5. A compound in accordance with claim 1, said compound being selected from the group consisting of Ac-RSVL-H (SEQ ID NO:

2), Ac-RSVL-CH₂Cl (SEQ ID NO;

3), Ac-RSVL-CH₂F (SEQ ID NO;

4), Ac-RSVL-CF₃ (SEQ ID NO;

5), Ac-RSVL-CONHEt (SEQ ID NO;

6), Ac-RSVL-CO₂Et (SEQ ID NO;

7), Ac-RSVL-2-thiazolyl (SEQ ID NO;

8), Ac-RSVL-2-benzothiazolyl (SEQ ID NO;

9), Ac-RSLL-H (SEQ ID NO;

10), Ac-RSLL-CH₂Cl (SEQ ID NO;

11), Ac-RSLL-CH₂F (SEQ ID NO;

12), Ac-RSLL-CF₃ (SEQ ID NO;

13), Ac-RSLL-CONHEt (SEQ ID NO;

14), Ac-RSLL-CO₂Et (SEQ ID NO;

15), Ac-RSLL-2-benzothiazolyl (SEQ ID NO;

16), Ac-RSLL-2-thiazolyl (SEQ ID NO;

17), Ac-RSLK-H (SEQ ID NO;

18), Ac-RSLK-CH₂Cl (SEQ ID NO;

19), Ac-RSLK-CH₂F (SEQ ID NO;

20), Ac-RSLK-CF₃ (SEQ ID NO;

21), Ac-RSLK-CONHEt (SEQ ID NO;

22), Ac-RSLK-CO₂Et (SEQ ID NO;

23), Ac-RSLK-2-thiazolyl (SEQ ID NO;

24), Ac-RSLK-2-benzothiazolyl (SEQ ID NO;

25), Ac-KSVL-H (SEQ ID NO;

26), Ac-KSVL-CH₂Cl (SEQ ID NO;

27), Ac-KSVL-CH₂F (SEQ ID NO;

28), Ac-KSVL-CF₃ (SEQ ID NO;

29), Ac-KSVL-CONHEt (SEQ ID NO;

30), Ac-KSVL-CO₂Et (SEQ ID NO;

31), Ac-KSVL-2-benzothiazolyl (SEQ ID NO;

32), Ac-KSVL-2-thiazolyl (SEQ ID NO;

33), Ac-RSVK-H (SEQ ID NO;

34), Ac-RSVK-CH₂F (SEQ ID NO;

35), Ac-RSVK-CH₂Cl (SEQ ID NO;

36), Ac-RSVK-CF₃ (SEQ ID NO;

37), Ac-RSVK-CONHEt (SEQ ID NO;

38), Ac-RSVK-CO₂Et (SEQ ID NO;

39), Ac-RSVK-2-benzothiazolyl (SEQ ID NO;

40) and Ac-RSVK-2-thiazolyl (SEQ ID NO;

41).

6. A compound in accordance with claim 1, said compound being selected from the group consisting of Cbz-RSVL-H (SEQ ID NO:

42), Cbz-RSVL-CH₂F (SEQ ID NO;

43), Cbz-RSVL-CH₂Cl (SEQ ID NO;

44), Cbz-RSVL-CF₃ (SEQ ID NO;

45), Cbz-RSVL-CONHEt (SEQ ID NO;

46), Cbz-RSVL-CO₂Et (SEQ ID NO;

47), Cbz-RSVL-2-thiazolyl (SEQ ID NO;

48), Cbz-RSVL-2-benzothiazolyl (SEQ ID NO;

49), Cbz-RSLL-H (SEQ ID NO;

50), Cbz-RSLL-CH₂F (SEQ ID NO;

51), Cbz-RSLL-CH₂Cl (SEQ ID NO;

52), Cbz-RSLL-CF₃ (SEQ ID NO;

53), Cbz-RSLL-CONHEt (SEQ ID NO;

54), Cbz-RSLL-CO₂Et(SEQ ID NO;

55), Cbz-RSLL-2-thiazolyl (SEQ ID NO;

56), Cbz-RSLL-2-benzothiazolyl (SEQ ID NO;

57), Cbz-RSLK-H (SEQ ID NO;

58), Cbz-RSLK-CH₂F (SEQ ID NO;

59), Cbz-RSLK-CH₂Cl (SEQ ID NO;

60), Cbz-RSLK-CF₃ (SEQ ID NO;

61), Cbz-RSLK-CONHEt (SEQ IDNO;

62), Cbz-RSLK-CO₂Et (SEQ ID NO;

64), Cbz-RSLK-2-thiazolyl (SEQ ID NO;

65), Cbz-RSLK-2-benzothiazolyl (SEQ ID NO;

66), Cbz-KSVL-H (SEQ ID NO;

67), Cbz-KSVL-CH₂F(SEQ ID NO;

68), Cbz-KSVL-CH₂Cl (SEQ ID NO;

69), Cbz-KSVL-CF₃ (SEQ ID NO;

69), Cbz-KSVL-CONHEt (SEQ ID NO;

70), Cbz-KSVL-CO₂Et (SEQ ID NO;

71), Cbz-KSVL-2-thiazolyl (SEQ ID NO;

72), Cbz-KSVL-2-benzothiazolyl (SEQ ID NO;

73), Cbz-RSVK-H (SEQ ID NO;

74), Cbz-RSVK-CH₂F (SEQ ID NO;

75), Cbz-RSVK-CH₂Cl (SEQ ID NO;

76), Cbz-RSVK-CF₃ (SEQ ID NO;

77), Cbz-RSVK-CONHEt (SEQ ID NO;

78), Cbz-RSVK-CO₂Et (SEQ ID NO;

79), Cbz-RSVK-2-thiazolyl (SEQ ID NO;

80) and Cbz-RSVK-2-benzothiazolyl (SEQ ID NO;

81).

7. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula:

8. A pharmaceutical composition in accordance with claim 7,

wherein

X is NH or N(C₁-C₄)alkyl;

and

n′

is 0 or 1.

9. A pharmaceutical composition in accordance with claim 7, wherein

R¹ is a member selected from the group consisting of (C₁-C₃)alkyl, aryl(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and aryl(C₁-C₃)alkoxy;

R² is selected from the group consisting of;

wherein

X is NH;

n′

is 0 or 1;

R¹¹, R¹⁴ and R¹⁵ are each H;

R¹² is selected from the group consisting of (C₁-C₄)alkyl, (C₂-C₈)heteroalkyl and aryl(C₁-C₂)alkyl; and

R¹³ is selected from the group consisting of H, CH₂Cl, CF₃, heteroaryl, CO₂R¹⁶ and CONHR¹⁶.

10. A pharmaceutical composition in accordance with claim 7, wherein R² is a radical of the formula:

wherein

X is NH, n′

is O, R¹¹ is H, R¹² is a member selected from the group consisting of 2-methyl-1-propyl, methyl, benzyl, 4-amino-1-butyl and 3-guanidino-1-propyl, and R¹³ is a member selected from the group consisting of H, CH₂Cl, CF₃, CONHEt, CO₂Et and 2-thiazolyl.

11. A pharmaceutical composition in accordance with claim 7, said compound being selected from the group consisting of Ac-RSVL-H (SEQ ID NO:

2), Ac-RSVL-CH₂Cl (SEQ ID NO;

3), Ac-RSVL-CH₂F (SEQ ID NO;

4), Ac-RSVL-CF₃ (SEQ ID NO;

5), Ac-RSVL-CONHEt (SEQ ID NO;

6), Ac-RSVL-CO₂Et (SEQ ID NO;

7), Ac-RSVL-2-thiazolyl (SEQ ID NO;

8), Ac-RSVL-2-benzothiazolyl (SEQ ID NO;

9), Ac-RSLL-H (SEQ ID NO;

10), Ac-RSLL-CH₂Cl (SEQ ID NO;

11), Ac-RSLL-CH₂F (SEQ ID NO;

12), Ac-RSLL-CF₃ (SEQ ID NO;

13), Ac-RSLL-CONHEt (SEQ ID NO;

14), Ac-RSLL-CO₂Et (SEQ IDNO;

15), Ac-RSLL-2-benzothiazolyl (SEQ ID NO;

16), Ac-RSLL-2-thiazolyl (SEQ ID NO;

17), Ac-RSLK-H (SEQ ID NO;

18), Ac-RSLK-CH₂Cl (SEQ ID NO;

19), Ac-RSLK-CH₂F (SEQ ID NO;

20), Ac-RSLK-CF₃ (SEQ ID NO;

21), Ac-RSLK-CONHEt (SEQ ID NO;

22), Ac-RSLK-CO₂Et (SEQ ID NO;

23), Ac-RSLK-2-thiazolyl (SEQ ID NO;

24), Ac-RSLK-2-benzothiazolyl (SEQ ID NO;

25), Ac-KSVL-H (SEQ ID NO;

26), Ac-KSVL-CH₂Cl (SEQ ID NO;

27), Ac-KSVL-CH₂F (SEQ ID NO;

28), Ac-KSVL-CF₃ (SEQ ID NO;

29), Ac-KSVL-CONHEt (SEQ ID NO;

30), Ac-KSVL-CO₂Et (SEQ ID NO;

31), Ac-KSVL-2-benzothiazolyl (SEQ ID NO;

32), Ac-KSVL-2-thiazolyl (SEQ ID NO;

33), Ac-RSVK-H (SEQ ID NO;

34), Ac-RSVK-CH₂F (SEQ ID NO;

35), Ac-RSVK-CH₂Cl (SEQ ID NO;

36), Ac-RSVK-CF₃ (SEQ ID NO;

37), Ac-RSVK-CONHEt (SEQ ID NO;

38), Ac-RSVK-CO₂Et (SEQ ID NO;

39), Ac-RSVK-2-benzothiazolyl (SEQ ID NO;

40) and Ac-RSVK-2-thiazolyl (SEQ ID NO;

41).

12. A pharmaceutical composition in accordance with claim 7, said compound being selected from the group consisting of Cbz-RSVL-H (SEQ ID NO:

42), Cbz-RSVL-CH₂F (SEQ ID NO;

43), Cbz-RSVL-CH₂Cl (SEQ ID NO;

44), Cbz-RSVL-CF₃ (SEQ ID NO;

45), Cbz-RSVL-CONHEt (SEQ ID NO;

46), Cbz-RSVL-CO₂Et (SEQ ID NO;

47), Cbz-RSVL-2-thiazolyl (SEQ ID NO;

48), Cbz-RSVL-2-benzothiazolyl (SEQ ID NO;

49), Cbz-RSLL-H (SEQ ID NO;

50), Cbz-RSLL-CH₂F (SEQ ID NO;

51), Cbz-RSLL-CH₂Cl (SEQ ID NO;

52), Cbz-RSLL-CF₃ (SEQ ID NO;

53), Cbz-RSLL-CONHEt (SEQ ID NO;

54), Cbz-RSLL-CO₂Et (SEQ ID NO;

55), Cbz-RSLL-2-thiazolyl (SEQ ID NO;

56), Cbz-RSLL-2-benzothiazolyl (SEQ ID NO;

57), Cbz-RSLK-H (SEQ ID NO;

58), Cbz-RSLK-CH₂F (SEQ ID NO;

59), Cbz-RSLK-CH₂Cl (SEQ ID NO;

60), Cbz-RSLK-CF₃ (SEQ ID NO;

61), Cbz-RSLK-CONHEt (SEQ ID NO;

62), Cbz-RSLK-CO₂Et (SEQ ID NO;

64), Cbz-RSLK-2-thiazolyl (SEQ ID NO;

65), Cbz-RSLK-2-benzothiazolyl (SEQ ID NO;

66), Cbz-KSVL-H (SEQ ID NO;

67), Cbz-KSVL-CH₂F (SEQ ID NO;

68), Cbz-KSVL-CH₂Cl (SEQ ID NO;

69), Cbz-KSVL-CF₃ (SEQ ID NO;

69), Cbz-KSVL-CONHEt (SEQ ID NO;

70), Cbz-KSVL-CO₂Et (SEQ ID NO;

71), Cbz-KSVL-2-thiazolyl (SEQ ID NO;

72), Cbz-KSVL-2-benzothiazolyl (SEQ ID NO;

73), Cbz-RSVK-H (SEQ ID NO;

74), Cbz-RSVK-CH₂F (SEQ ID NO;

75), Cbz-RSVK-CH₂Cl (SEQ ID NO;

76), Cbz-RSVK-CF₃ (SEQ ID NO;

77), Cbz-RSVK-CONHEt (SEQ ID NO;

78), Cbz-RSVK-CO₂Et (SEQ ID NO;

79), Cbz-RSVK-2-thiazolyl (SEQ ID NO;

80) and Cbz-RSVK-2-benzothiazolyl (SEQ ID NO;

81).