Modified cytotoxins and their therapeutic use

Patent metadata

Field	Value
Publication number	US-10286079-B2
Application number	US-201715466819-A
Country	US
Kind code	B2
Filing date	Mar 22, 2017
Priority date	Sep 22, 2015
Publication date	May 14, 2019
Grant date	May 14, 2019

Abstract

The present disclosure generally provides compounds useful for treating cancer. In some aspects, the disclosure provides small-molecule cytotoxins that are chemically modified to include one or more moieties that include hydrophobic portions. In some embodiments, the disclosure provides small-molecule cytotoxins that are chemically modified with fatty acid-containing moieties. In some aspects, the disclosure provides compositions, such as pharmaceutical compositions, that include such modified small-molecule cytotoxins and a protein. In some embodiments, the protein is albumin or an albumin mimetic. Further, the disclosure provides various uses of these compounds and compositions.

First claim

The invention claimed is:

1. A compound of formula (1)
A 1 -X 1 —X 2 -A 2   (I)

wherein:
A 1 is a carboxylic acid group, a carboxylate anion, or a carboxylate ester of the formula —COOR a , wherein R a is an alkyl or an alkoxylate group;
A 2 is a paclitaxel moiety;
X 1 is C 12-22 straight-chain alkylene or C 12-22 straight-chain alkenylene, wherein A 1 is separated from X 2 by at least 6 carbon atoms; and
X 2 is an organic group, wherein the organic group comprises one or more moieties selected from the group consisting of: —C(═O)—, —O—C(═O)—, —NH—C(═O)—, one or more units formed from alkylene glycols, one or more units formed from alkanol amines, one or more units formed from amino acids, one or more units formed from hydroxyl acids, and combinations thereof, and wherein the organic group comprises from 1 to 100 carbon atoms.

2. The compound of claim 1 , wherein A 1 is a carboxylic acid group.

3. The compound of claim 1 , wherein the paclitaxel moiety is a moiety of the formula:

4. The compound of claim 1 , wherein X 1 is C 12-22 straight-chain alkylene group.

5. The compound of claim 1 , wherein X 2 is —C(═O)—.

6. A pharmaceutical composition comprising:
a compound of claim 1 ; and
a protein, wherein the protein is human serum albumin or a protein whose sequence is at least 50% equivalent to that of human serum albumin.

7. The pharmaceutical composition of claim 6 , wherein the protein is human serum albumin.

8. The pharmaceutical composition of claim 6 , further comprising a carrier.

9. The pharmaceutical composition of claim 8 , wherein the carrier comprises water.

10. The pharmaceutical composition of claim 9 , wherein the compound and the protein are non-covalently associated with each other with a binding constant (K b ) of at least 10 2 M −1 .

11. The pharmaceutical composition of claim 8 , wherein the compound and the protein are solvated by the carrier.

12. A method of treating cancer, comprising:
administering to a subject a composition of claim 6 .

13. The compound of claim 1 , wherein X 1 is C 14-22 straight-chain alkylene.

14. The compound of claim 1 , wherein X 1 is C 14-22 straight-chain alkenylene.

15. A pharmaceutical composition comprising:
a compound of claim 13 ; and
a protein, wherein the protein is human serum albumin or a protein whose sequence is at least 50% equivalent to that of human serum albumin.

16. A pharmaceutical composition comprising:
a compound of formula (1)
A 1 -X 1 —X 2 -A 2   (I)

wherein:
A 1 is a carboxylic acid group, a carboxylate anion, or a carboxylate ester;
A 2 is a paclitaxel moiety;
X 1 is C 12-22 hydrocarbylene, wherein A 1 is separated from X 2 by at least 6 carbon atoms; and
X 2 is an organic group, wherein the organic group comprises one or more moieties selected from the group consisting of: —C(═O)—, —O—C(═O)—, —NH—C(═O)—, one or more units formed from alkylene glycols, one or more units formed from alkanol amines, one or more units formed from amino acids, one or more units formed from hydroxyl acids, and combinations thereof, and wherein the organic group comprises from 1 to 100 carbon atoms; and
a protein, wherein the protein is human serum albumin or a protein whose sequence is at least 50% equivalent to that of human serum albumin.

Assignees

• Univ California
• Vybyl Holdings Inc

Inventors

• Callmann Cassandra E
• Thompson Matthew P
• Gianneschi Nathan C
• Leguyader Clare L M
• Bertin Paul A

Classifications

• A61K47/542 Primary

  Carboxylic acids, e.g. a fatty acid or an amino acid · CPC title

• A61K47/643

  Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL] · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• C07D491/044

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title