Inhibitors of growth factor activation enzymes

Patent metadata

Field	Value
Publication number	US-11130780-B2
Application number	US-201615556804-A
Country	US
Kind code	B2
Filing date	Mar 2, 2016
Priority date	Mar 9, 2015
Publication date	Sep 28, 2021
Grant date	Sep 28, 2021

Abstract

The present invention generally relates to compounds that are useful for inhibiting one or more of hepatocyte growth factor activator, matriptase, hepsin, Factor Xa, or thrombin. The present invention also relates to various methods of using the inhibitor compounds including treating a malignancy, a pre-malignant condition, or cancer by administering an effective amount of the inhibitor to a subject in need thereof.

First claim

What is claimed is:

1. A compound of Formula (II):
Y—P 4 —P 3 —P 2 —P 1 —Z  (II)

wherein
Y is acetyl, tert-butyloxycarbonyl, benzyloxymethyl acetyl, carboxybenzyl, fluorenylmethoxycarbonyl (FMOC), benzyl, or a fluorophore;
P 1 is a residue of an amino acid selected from the group consisting of Arg and D-Arg;
P 2 is a residue of an amino acid selected from the group consisting of Leu and hLeu;
P 3 is a residue of an amino acid selected from the group consisting of Arg, Lys, Trp, Leu, Gln, Phe, His, hArg, D-Trp, His(3-Bom), and L-Phe(NO 2 );
P4 is a residue of an amino acid selected from the group consisting of Arg, Lys, Trp, Ser, Phe, Thr, Asn, His(3-Bom), and D-Trp; and
Z is a

or a benzothiazole of Formula (IV) or (V)

wherein
J 1 is C(O), SO 2 , CH 2 , or heterocyclo;
K 1 is a D- or L-amino acid, wherein the C-terminus is —COOH, —C(O)NH 2 , —OH, —OR 10 , —NH 2 , —NR 11 R 12 , —H, or heterocyclo;
R 10 is C 1 to C 12 alkyl, cycloalkyl, alkylaryl, or aryl;
R 11 and R 12 are each independently H, C 1 to C 12 alkyl, cycloalkyl, alkylaryl, aryl, or heterocyclo; and R 11 and R 12 optionally form a ring; and
L 1 is H, alkyl, cycloalkyl, alkylaryl, benzyl, substituted benzyl, 2- or 3- or 4-piperdinyl, 2- or 3- or 4-pyridinyl, aryl, heterocyclo, or heteroaryl.

2. The compound of claim 1 wherein Y is acetyl and/or Z is

3. The compound of claim 1 wherein P 1 is an amino acid residue of Arg; P 2 is an amino acid residue of Leu; P 3 is an amino acid residue of His, Gln, Arg, Lys, Leu, Phe, or Trp; and P 4 is an amino acid residue of Ser, Lys, Phe, Trp, or His(3-Bom).

4. The compound of claim 2 wherein P 1 is an amino acid residue of Arg; P 2 is an amino acid residue of Leu; P 3 is an amino acid residue of Arg, Leu, Trp, Phe, His, Gln, or Lys; and P 4 is an amino acid residue of Phe, Trp, Ser, Lys, or His(3-Bom).

5. The compound claim 1 wherein P 1 is an amino acid residue of Arg; P 2 is an amino acid residue of Leu; P 3 is an amino acid residue of Leu, Trp, Phe, His, Gln, or Lys; and P 4 is an amino acid residue of Phe, Lys, or His(3-Bom).

6. The compound of claim 1 wherein P 4 -P 3 -P 2 -P 1 of Formula (II) is a tetrapeptide selected from the group consisting of SEQ ID NO 1, SEQ ID NO 2, SEQ ID NO 3, SEQ ID NO 5, SEQ ID NO 6, SEQ ID NO 7, SEQ ID NO 8, SEQ ID NO 9, SEQ ID NO 10, SEQ ID NO 11, SEQ ID NO 12, SEQ ID NO 14, SEQ ID NO 15, SEQ ID NO 16, SEQ ID NO 17, and SEQ ID NO 18.

7. The compound of claim 1 wherein Z is a benzothiazole of Formula (IV) or Formula (V).

8. The compound of claim 1 wherein L 1 is a substituted benzyl group.

9. The compound of claim 2 wherein Z is

10. The compound of claim 6 wherein Y is acetyl and Z is a

11. The compound of claim 1 , wherein the compound is selected from the group consisting of:

12. A method of inhibiting tumor progression comprising administering to the subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 .

13. A method of treating a cancer in a subject comprising administering to the subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 .

14. The method of claim 13 , wherein the cancer is selected from the group consisting of breast, ovarian, prostate, endometrial, colon, pancreatic, head and neck, gastric, renal, brain, liver, bladder, kidney, lung, esophageal, leukemias, multiple myeloma, lymphoma, and melanoma.

15. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 .

16. A fluorescent imaging composition comprising a compound of Formula (II) of claim 1 and a fluorophore selected from the group consisting of Cy3, Cy3.5, Cy5, Cy5.5, Cy7, and Cy7.5.

17. A method of detecting imaging cancer comprising:
administering to a subject the fluorescent imaging composition of claim 16 ;
detecting fluorescence of the fluorescent imaging composition within the body of the subject,
wherein fluorescence of the fluorescent imaging composition indicates the existence of cancer.

18. A radiolabeled imaging composition comprising a compound of Formula (II) of claim 1 and a radioisotope selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 75 Br, 124 I, 125 I, and 131 I.

19. A method of imaging cancer comprising:
administering to a subject the radiolabeled imaging composition of claim 18 ; and
detecting radiation of the radiolabeled imaging composition within the body of the subject,
wherein the radiation of the radiolabeled imaging composition indicates the existence of cancer.

20. The compound of claim 1 wherein Z is a benzothiazole of Formula (IV).

21. The compound of claim 1 wherein P 2 forms a bond with P 4 to form a cyclic peptide.

22. The compound of claim 1 wherein the compound has the following formula:

wherein
Y is acetyl;
P 2 is a residue of an amino acid selected from the group consisting of Leu and hLeu;
P 3 is a residue of an amino acid selected from the group consisting of Arg, Lys, Trp, Leu, Gln, Phe, His, His(3-Bom), and L-Phe(NO 2 );
P 4 is a residue of an amino acid selected from the group consisting of Arg, Lys, Trp, Ser, Phe, His(3-Bom); and
Z is

wherein
J 1 is C(O), SO 2 , CH 2 , or heterocyclo,
K 1 is a D- or L-amino acid, wherein the C-terminus is —COOH, —C(O)NH 2 , —OH, —OR 10 , —NH 2 , —NR 11 R 12 , —H, or heterocyclo;
R 10 is C 1 to C 12 alkyl, cycloalkyl, alkylaryl, or aryl;
R 11 and R 12 are each independently H, C 1 to C 12 alkyl, cycloalkyl, alkylaryl, aryl, or heterocyclo; and R 11 and R 12 optionally form a ring; and
L 1 is H, alkyl, cycloalkyl, alkylaryl, benzyl, substituted benzyl, 2- or 3- or 4-piperdinyl, 2- or 3- or 4-pyridinyl, aryl, heterocyclo, or heteroaryl.

23. A compound of Formula (II):
Y—P 4 —P 3 —P 2 —P 1 —Z  (II)

wherein
Y is acetyl, tert-butyloxycarbonyl, benzyloxymethyl acetyl, carboxybenzyl, fluorenylmethoxycarbonyl (FMOC), benzyl, or a fluorophore;
P 1 is a residue of Arg;
P 2 is a residue of an amino acid selected from the group consisting of Leu or hLeu

Assignees

• Janetka James W
• Han Zhenfu
• Harris Peter
• Karmakar Partha
• Univ Washington

Inventors

• Janetka James W
• Han Zhenfu
• Harris Peter
• Karmakar Partha

Classifications

• C07K5/1019

  with the first amino acid being basic · CPC title

• C07K5/101

  the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu · CPC title

• C07K5/1013

  the side chain containing O or S as heteroatoms, e.g. Cys, Ser · CPC title

• C07K5/0817

  the first amino acid being Arg · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title