Dolastatin peptides

• US 6,323,315 B1
• Filed: 03/31/2000
• Issued: 11/27/2001
• Est. Priority Date: 09/10/1999
• Status: Expired due to Fees

• Current Assignee: BASF AG (BASF SE), Arizona Board of Regents (University of Arizona)
• Original Assignee: BASF AG (BASF SE), Arizona Board of Regents (University of Arizona)
• Inventors: Williams, Michael D., Srirangam, Jayaram K., Kling, Andreas, Haupt, Andreas, Pettit, George R., Barlozzari, Teresa, Janssen, Bernd, Durkin, Kieran P. M.
• Primary Examiner(s): Oswecki, Jane C.
• Application Number:
  US09/539,935
• Time in Patent Office: 606 Days
• Field of Search: 530/330, 530/331, 548/517, 548/518, 548/530
• US Class Current: 530/330
• 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 5/0205 containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link

Abstract

The present invention provides compounds of the formula

where R₁-R₅ are each, independently, a hydrogen atom or a normal or branched C₁-C₆-alkyl group; A is a methionyl, phenylalanyl or phenylglycyl residue; n is 0 or 1; R₆ is a hydrogen atom; and R₇ is a carbocylic group, an aromatic group, a C₁-C₄-alkyl group, a pyridylalkyl group or a heterocyclic group. In another embodiment, R₆ is benzyl or —C(O)OR₈, where R₈ is a C₁-C₆-alkyl group, and R₇ is a heteroaromatic group, such as a 2-thiazolyl group.

Claims

1. The compound of the formula

or a salt thereof with a pharmaceutically acceptable acid, wherein

R₁-R₅ are each, independently, a hydrogen atom or a normal or branched C₁-C₆-alkyl group;

A is a phenylalanyl or phenylglycyl residue;

n is 0 or 1;

R₆is a hydrogen atom; and

R₇ is selected from the group consisting of t-butyl, isopropyl, methyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(3-pyridyl)ethyl, 4-pyridyl,

or

R₆ is benzyl or —

C(O)OR₈, wherein R₈ is a C₁-C₆-alkyl group; and

R₇ is a 2-thiazolyl group.

2. The compound of claim 1 wherein R₁ and R₂ are each a methyl group, R₃ is an isopropyl or sec-butyl group, R₄ is an isopropyl, sec-butyl or isobutyl group, and R₅ is a sec-butyl group.

4. The compound of claim 2 wherein R₁ and R₂ are each methyl, R₃ and R₄ are each isopropyl, R₅ is sec-butyl, n is 0, R₆ is a hydrogen atom and R₇ is selected from the group consisting of t-butyl, isopropyl, methyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(3-pyridyl)ethyl, 4-pyridyl,

5. The compound of claim 2 wherein R₁ and R₂ are each methyl;

R₃ is isopropyl;

R₄ and R₅ are each sec-butyl;

n is 0;

R₆ is a hydrogen atom; and

R₇ is

6. The compound of claim 2 wherein R₁ and R₂ are each methyl;

R₃ is isopropyl;

R₄ is isopropyl or sec-butyl;

R₅ is sec-butyl;

n is 0;

R₆ is a benzyl group or —

C(O)OCH₃; and

R₇ is a 2-thiazolyl group.

7. The compound of claim 2 wherein R₁ and R₂ are each methyl;

R₃ is isopropyl;

R₄ is isopropyl;

R₅ is sec-butyl;

n is 1;

A is a phenylalanyl residue;

R₆ is a hydrogen atom; and

R₇ is

3. The compound of the formula

or a salt thereof with a pharmaceutically acceptable acid, wherein R₁ and R₂ are each methyl;

R₃ and R₄ are each isopropyl;

R₅ is sec-butyl;

n is 1;

A is a methionyl residue;

R₆ is a hydrogen atom; and

R₇ is selected from the group consisting of

8. The compound of the formula

or a salt thereof with a pharmaceutically acceptable acid, wherein

R₁-R₅ are each, independently, a hydrogen atom or a normal or branched C₁-C₆-alkyl group;

A is a methionyl, phenylalanyl or phenylglycyl residue;

n is 0 or 1;

R₆ is a hydrogen atom; and

R₇ is an aromatic group.

9. The compound of claim 8 wherein R₇ is

10. The compound of claim 9 wherein R₁ and R₂ are each a methyl group;

R₃ and R₄ are each an isopropyl group;

R₅ is a sec-butyl group;

n is 1; and

A is a methionyl residue.

11. A compound of the formula

or a salt thereof with a pharmaceutically acceptable acid, wherein

R₁-R₅ are each, independently, a hydrogen atom or a normal or branched C₁-C₆-alkyl group;

A is a methionyl, phenylalanyl or phenylglycyl residue;

n is 0 or 1; and

12. The compound of claim 11 wherein R₆ and R₇ are each a methylene group.

13. The compound of claim 12 wherein R₁ and R₂ are each a methyl group;

R₃ and R₄ are each an isopropyl group;

R₅ is a sec-butyl group; and

n is 0.

14. The compound of the formula

or a salt thereof with a pharmaceutically acceptable acid, wherein

R₁-R₅ are each, independently, a hydrogen atom or a normal or branched C₁-C₆-alkyl group;

A is a methionyl, phenylalanyl or phenylglycyl residue;

n is 0 or 1;

R₆ is a hydrogen atom; and

R₇ is selected from the group consisting of t-butyl, isopropyl, methyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(3-pyridyl)ethyl,

or

R₆ is benzyl or —

C(O)OR₈, wherein R₈ is a C₁-C₆-alkyl group; and

R₇ is a 2-thiazolyl group.

15. The compound of claim 14 wherein R₁ and R₂ are each a methyl group, R₃ is an isopropyl or sec-butyl group, R₄ is an isopropyl, sec-butyl or isobutyl group, and R₅ is a sec-butyl group.

16. The compound of claim 14 wherein R₁ and R₂ are each methyl, R₃ and R₄ are each isopropyl, R₅ is sec-butyl, n is 0, R₆ is a hydrogen atom and R₇ is selected from the group consisting of t-butyl, isopropyl, methyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(3-pyridyl)ethyl,

17. The compound of claim 14 wherein R₁ and R₂ are each methyl;

R₃ is isopropyl;

R₄ and R₅ are each sec-butyl;

n is 0;

R₆ is a hydrogen atom; and

R₇ is

18. The compound of claim 14 wherein R₁ and R₂ are each methyl;

R₃ is isopropyl;

R₄ is isopropyl or sec-butyl;

R₅ is sec-butyl;

n is 0;

R₆ is a benzyl group or —

C(O)OCH₃; and

R₇ is a 2-thiazolyl group.