TARGETED DELIVERY OF CHEMOTHERAPEUTIC AGENTS

• US 20100240594A1
• Filed: 03/19/2010
• Published: 09/23/2010
• Est. Priority Date: 03/20/2009
• Status: Abandoned Application

• Current Assignee: Burnham Institute For Medical Research
• Original Assignee: Burnham Institute For Medical Research
• Inventors: Pellecchia, Maurizio
• Application Number:
  US12/728,077
• Publication Number:
  US 20100240594A1
• Time in Patent Office: Days
• US Class Current: 514/19.300
• CPC Class Codes: A61K 38/00 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 Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

The disclosure provides compounds and compositions, and methods of using these compounds and compositions, for the targeted delivery of chemotherapeutic agents.

Claims

1. A compound of Formula I:

EPH_T-L-D 

 

(I),

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein;

EPH-T is an Eph receptor binding compound;

L is a linking group; and

D is a chemotherapeutic agent.

2. The compound of claim 1, wherein the EPH-T is a YSA peptide having Formula II:

3. The compound of claim 2, wherein the YSA peptide having Formula II or amino acid sequence YSAYPDSVPMMS, is substituted with any of the amino acid substitutions as follows:

each Y is optionally S, T, C, N or Q;

each S is optionally T, C, Y, N or Q;

each A is optionally G, V, L, nL, I, M, F, W or P;

each P is optionally G, A, V, L, nL, I, M, F or W;

each D is optionally E;

each V is optionally G, A, L, nL, I, M, F, W or P; and

each M is optionally G, A, V, L, nL, I, F, W or P,

wherein;

G is glycine;

A is alanine;

V is valine;

L is leucine;

nL is nor-Leucine;

I is isoleucine;

M is methionine;

F is phenylalanine;

W is tryptophan;

P is proline;

S is serine;

T is threonine;

C is cysteine;

Y is tyrosine;

N is asparagine;

Q is glutamine;

D is aspartic acid;

E is glutamic acid;

K is lysine;

R is arginine; and

H is histidine.

4. The compound of claim 2, wherein the YSA peptide having Formula II or amino acid sequence YSAYPDSVPMMS, has amino acid sequence:

YSAYPDSVPnLnLS, wherein nL is nor-Leucine.

5. The compound of claim 1, wherein the linking group has Formula III or IV:

6. The compound of claim 5, wherein m is 2;

and n is 2.

7. The compound of claim 1, wherein the chemotherapeutic agent is taxol, doxorubicin, taxotere, campotechin, or etoposide.

8. The compound of claim 1, wherein the compound of Formula I has Formula V:

9. The compound of claim 1, wherein the compound of Formula has Formula VI:

10. The compound of claim 1, wherein the compound of Formula I has Formula VII:

15. A pharmaceutical composition comprising the compound of Formula I of claim 1, and a pharmaceutically acceptable solvent.

16. A method of treating cancer, the method comprising the steps of administering a pharmacologically effective amount of the pharmaceutical composition of claim 15 to a patient in need thereof.

17. A method of targeting delivery of chemotherapeutic agents to the Eph receptor, the method comprising the steps of contacting the Eph receptor with the compound of Formula I of claim 1.

18. A method of preparing the compound of Formula I of claim 1:

EPH_T-L-D 

 

(I),

the method comprising the steps of

a) coupling the EPH_T (Eph receptor binding compound) to an alkynoic acid;

b) coupling the D (chemotherapeutic agent) to an azide; and

c) reacting the EPH-T (Eph receptor binding compound) coupled to an alkynoic acid with the D (chemotherapeutic agent) coupled to an azide in a 1,3-dipolar cycloaddition reaction to form a 1,4-disubstituted-1,2,3-triazole compound of Formula I.

19. The method of claim 18, wherein the EPH-T is a YSA peptide having Formula II:

20. The method of claim 19, wherein the YSA peptide having Formula II or amino acid sequence YSAYPDSVPMMS, is substituted with any of the amino acid substitutions as follows:

each Y is optionally S, T, C, N or Q;

each S is optionally T, C, Y, N or Q;

each A is optionally G, V, L, nL, I, M, F, W or P;

each P is optionally G, A, V, L, nL, I, M, F or W;

each D is optionally E;

each V is optionally G, A, L, nL, I, M, F, W or P; and

each M is optionally G, A, V, L, nL, I, F, W or P,

wherein;

G is glycine;

A is alanine;

V is valine;

L is leucine;

nL is nor-Leucine;

I is isoleucine;

M is methionine;

F is phenylalanine;

W is tryptophan;

P is proline;

S is serine;

T is threonine;

C is cysteine;

Y is tyrosine;

N is asparagine;

Q is glutamine;

D is aspartic acid;

E is glutamic acid;

K is lysine;

R is arginine; and

H is histidine.

21. The method of claim 19, wherein the YSA peptide having Formula II or amino acid sequence YSAYPDSVPMMS, has amino acid sequence:

YSAYPDSVPnLnLS, wherein nL is nor-Leucine.

22. The method of claim 18, wherein the 1,4-disubstituted-1,2,3-triazole compound has Formula III or IV:

23. The method of claim 22, wherein m is 2;

and n is 2.

24. The method of claim 18, wherein the chemotherapeutic agent is taxol, doxorubicin, taxotere, campotechin, or etoposide.

25. The method of claim 18, wherein the compound of Formula I has Formula V:

26. The method of claim 18, wherein the compound of Formula I has Formula VI:

27. The method of claim 18, wherein the compound of Formula I has Formula VII:

28. The method of claim 18, wherein the coupling of the EPH_T (Eph receptor binding compound) to an alkynoic acid provides a compound of Formula VIII:

29. The method of claim 18, wherein the coupling of the D (chemotherapeutic agent) to an azide provides a compound of Formula IX:

30. The method of claim 18, wherein the coupling of the D (chemotherapeutic agent) to an azide provides a compound of formula X:

31. The method of claim 18, wherein the coupling of the D (chemotherapeutic agent) to an azide provides a compound of formula XI:

11. A compound of Formula VIII:

12. A compound of Formula IX:

13. A compound of formula X:

14. A compound of formula XI: