Quinstatin compounds

Patent metadata

Field	Value
Publication number	US-2018371012-A1
Application number	US-201615747077-A
Country	US
Kind code	A1
Filing date	Jul 22, 2016
Priority date	Jul 24, 2015
Publication date	Dec 27, 2018
Grant date	—

Abstract

The present disclosure relates to Quinstatin compounds, pharmaceutical compositions comprising such compounds, kits, and methods for using such compounds or pharmaceutical compositions.

First claim

1 . A compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, a Protecting Group or a Linker Unit;
R 2 is selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl or (C 2 -C 6 ) alkynyl;
R 3 is H or (C 1 -C 6 ) alkyl; and
X is a bicyclic heterocyclic ring system selected from quinolinyl, isoquinolinyl, 1,5-naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, 2,7-naphthyridinyl, 1,8-naphthyridinyl, 2,6-naphthyridinyl, phthalazinyl, 2H-chromenyl, 1H-1,5-benzodiazepinyl, 1,2,3-benzotriazinyl and 2,5-benzodiazocinyl, wherein the bicyclic heterocyclic ring system is unsubstituted or substituted with 1, 2 or 3 substituent(s) selected from (C 1 -C 6 ) alkoxy, methylene dioxy, hydroxyl, O-Protecting Group and O-Linker Unit.

2 .- 5 . (canceled)

6 . The compound of claim 1 , wherein the compound has formula (Ia):

7 . The compound of claim 1 , wherein the compound has formula (Ib):

8 . The compound of claim 1 , wherein the compound has formula (Ic):

9 . The compound of claim 1 , wherein the compound has formula (Id):

10 . The compound of claim 1 , wherein the compound has formula (Ie):

11 . The compound of claim 1 , wherein the compound has formula (If):

12 . The compound of claim 1 , wherein the compound has formula (Ig):

13 . The compound of claim 1 , wherein R 1 is H, (C 1 -C 6 ) alkyl or a Linker Unit.

14 .- 23 . (canceled)

24 . The compound of claim 1 , wherein R 2 is H or (C 1 -C 6 ) alkyl.

25 .- 31 . (canceled)

32 . The compound of claim 1 , wherein the Linker Unit has formula:
A a W w Y y , wherein A a is maleimidocaproyl, W w is Valine-Citrulline and Y y is p-aminobenzyloxycarbonyl.

33 .- 34 . (canceled)

35 . A compound selected from the group consisting of:

and
pharmaceutically acceptable salts thereof.

36 .- 42 . (canceled)

43 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

44 .- 45 . (canceled)

46 . A method for killing or inhibiting the proliferation of tumor cells or cancer cells comprising treating the tumor cells or cancer cells with a compound of claim 1 , or a pharmaceutical composition of claim 43 , in an amount effective to kill or inhibit the proliferation of the tumor cells or cancer cells.

47 . A method for treating cancer in a patient in need thereof comprising administering to the patient a compound of claim 1 , or a pharmaceutical composition of claim 43 , wherein the compound or pharmaceutical composition is administered in an amount effective to treat cancer.

48 .- 50 . (canceled)

51 . A method of determining inhibition of cellular proliferation by a compound, comprising contacting cells in a cell culture medium with the compound of claim 1 , and measuring the cytotoxic activity of the compound, whereby proliferation of the cells is inhibited.

52 . A method of inhibiting the growth of tumor cells that overexpress a tumor-associated antigen comprising administering to a patient the compound of claim 1 conjugated to an antibody that is specific for said tumor-associated antigen, and optionally a second therapeutic agent wherein the compound and the second therapeutic agent are each administered in amounts effective to inhibit the growth of tumor cells in the patient.

53 .- 56 . (canceled)

57 . An article of manufacture comprising the compound of claim 1 , a container, and a package insert or label indicating that the compound can be used to treat cancer characterized by the overexpression of at least one tumor-associated antigen.

Assignees

• Pettit George Robert
• Melody Noeleen
• Univ Arizona State

Inventors

• Pettit George Robert
• Melody Noeleen

Classifications

• A61K38/00

  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 title

• C07K5/06043

  Leu-amino acid · CPC title

• C07K5/0205 Primary

  containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K7/02

  Linear peptides containing at least one abnormal peptide link · CPC title