Modified cytotoxins and their therapeutic use

Patent metadata

Field	Value
Publication number	US-10023581-B2
Application number	US-201615271822-A
Country	US
Kind code	B2
Filing date	Sep 21, 2016
Priority date	Sep 22, 2015
Publication date	Jul 17, 2018
Grant date	Jul 17, 2018

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 (I)
A 1 -X 1 —X 2 -A 2   (I)

wherein:
A 2 is a paclitaxel moiety; and
—X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) n1 —C(═O)—H, wherein n1 is an integer from 12 to 24; or — 2 —X 1 -A 1 is C(═O)—(CH 2 ) 7 —CH═CH—(CH 2 ) 7 —C(═O)—OH.

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

3. The compound of claim 1 , which is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

4. 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.

5. The pharmaceutical composition of claim 4 , wherein the protein is human serum albumin.

6. The pharmaceutical composition of claim 4 , further comprising a carrier.

7. The pharmaceutical composition of claim 6 , wherein the carrier comprises water.

8. A method of treating cancer, comprising:
administering to a subject a composition of claim 4 .

9. The compound of claim 2 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) n1 —C(═O)—OH, wherein n1is an integer from 12 to 24.

10. The compound of claim 1 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) 14 —C(═O)—OH.

11. The compound of claim 1 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) 16 —C(═O)—OH.

12. The compound of claim 1 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) 18 —C(═O)—OH.

13. The compound of claim 1 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) 7 —CH═CH—(CH 2 ) 7 —C(═O)—OH.

14. The compound of claim 2 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) 14 —C(═O)—OH.

15. The compound of claim 2 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) 18 —C(═O)—OH.

16. The compound of claim 2 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) 7 —CH═CH—(CH 2 ) 7 —C(═O)—OH.

17. The compound of claim 1 , which is a compound of the formula:

18. A pharmaceutical composition comprising:
a compound of claim 3 ; 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.

19. A pharmaceutical composition comprising:
a compound of claim 17 ; 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.

20. A method of treating cancer, comprising:
administering to a subject a composition of claim 18 .

21. A method of treating cancer, comprising:
administering to a subject a composition of claim 19 .

Assignees

• Univ California
• Vybyl Holdings Inc

Inventors

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

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D491/22

  in which the condensed system contains four or more hetero rings · CPC title

• C07D491/044 Primary

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

• C07D305/14 Primary

  condensed with carbocyclic rings or ring systems · CPC title