IP Library › Granted Patent US 7,498,298

Granted Patent B2

US 7,498,298 · App. 10/983,340 · Granted Mar 3, 2009

Monomethylvaline compounds capable of conjugation to ligands

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Quick Facts

Patent No.: US 7,498,298
App. No.: 10/983,340
Granted: Mar 3, 2009
Kind: B2

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Abstract

Auristatin peptides, including MeVal-Val-Dil-Dap-Norephedrine (MMAE) and MeVal-Val-Dil-Dap-Phe (MMAF), were prepared and attached to Ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting ligand drug conjugates were active in vitro and in vivo.

Claims (147)

1. A compound having the formula:

wherein:

R 2 is selected from —H and —C 1 -C 8 alkyl;

R 3 is selected from —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);

R 4 is selected from —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle) wherein R 5 is selected from —H and -methyl; or R 4 and R 5 jointly have the formula —(CR a R b ), wherein R a and R b are independently selected from —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;

R 6 is selected from —H and —C 1 -C 8 alkyl;

R 7 is selected from —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);

each R 8 is independently selected from —H, —OH, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle and —O—(C 1 -C 8 alkyl);

R 9 is selected from —H and —C 1 -C 8 alkyl;

R 10 is selected from aryl group and —C 3 -C 8 heterocycle;

Z is —S—, —NH—, or —NR 12 —, wherein R 12 is C 1 -C 8 alkyl;

R 11 is selected from —H, C 1 -C 20 alkyl, aryl, —C 3 -C 8 heterocycle, —(R 13 O) m —R 14 , and —(R 13 O) m —CH(R 15 ) 2 ;

m is an integer ranging from 1 to 1000;

R 13 is —C 2 -C 8 alkyl;

R 14 is —H or —C 1 -C 8 alkyl;

each occurrence of R 15 is independently —H, —COOH, —(CH 2 ) n —N(R 6 ) 2 , —(CH 2 ) n —SO 3 H, or —(CH 2 ) n —SO 3 —C 1 -C 8 alkyl;

each occurrence of R 16 is independently —H, —C 1 -C 8 alkyl, or —(CH 2 ) n —COOH; and

n is an integer ranging from 0 to 6;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof.

5. A compound having the formula:

wherein the wavy line indicates H or a covalent linkage to a Linker Unit or a Ligand unit selected from the group consisting of a protein, a polypeptide and a peptide,

and independently at each location:

R 2 is selected from —H and —C 1 -C 8 alkyl;

R 4 is selected from —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle) wherein R 5 is selected from —H and -methyl; or R 4 and R 5 jointly have the formula —(CR a R b ) n — wherein R a and R b are independently selected from —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;

R 6 is selected from —H and —C 1 -C 8 alkyl;

each R 8 is independently selected from —H, —OH, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle and —O—(C 1 -C 8 alkyl);

R 9 is selected from —H and —C 1 -C 8 alkyl;

R 10 is selected from aryl group and —C 3 -C 8 heterocycle;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 having the formula:

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 5 having the formula:

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 5 having the formula:

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 5 having the formula:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 5 wherein Z is —NH, R 11 is (R 13 O) 2 —CH(R 15 ) 2 , wherein R 15 is —(CH 2 ) n —N(R 16 ) 2 , and R 16 is —C 1 -C 8 alkyl or —(CH 2 ) n —COOH.

12. The compound of claim 5 wherein Z is —NH, R 11 is (R 13 O) m —CH(R 15 ) 2 , wherein R 15 is —(CH 2 ) n —SO 3 H.

13. A compound having the formula:

wherein,

independently at each location:

R 2 is selected from H and —C 1 -C 8 alkyl;

R 4 is selected from —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle) wherein R 5 is selected from —H and -methyl; or R 4 and R 5 jointly have the formula —(CR a R b ) n — wherein R a and R b are independently selected from —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;

R 6 is selected from —H and —C 1 -C 8 alkyl;

each R 8 is independently selected from —H, —OH, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle and —O—(C 1 -C 8 alkyl);

R 9 is selected from —H and —C 1 -C 8 alkyl;

R 10 is selected from aryl group and —C 3 -C 8 heterocycle;

or a pharmaceutically acceptable salt thereof.

14. A compound having the formula:

wherein,

independently at each location:

R 2 is selected from H and —C 1 -C 8 alkyl;

R 4 is selected from —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle) wherein R 5 is selected from —H and -methyl; or R 4 and R 5 jointly have the formula —(CR a R b ) n — wherein R a and R b are independently selected from —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;

R 6 is selected from —H and —C 1 -C 8 alkyl;

each R 8 is independently selected from —H, —OH, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle and —O—(C 1 -C 8 alkyl);

R 9 is selected from —H and —C 1 -C 8 alkyl;

R 10 is selected from aryl group and —C 3 -C 8 heterocycle;

or a pharmaceutically acceptable salt thereof.

15. A compound having the formula:

wherein,

independently at each location:

R 2 is selected from H and —C 1 -C 8 alkyl;

R 4 is selected from —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle) wherein R 5 is selected from —H and -methyl; or R 4 and R 5 jointly have the formula —(CR a R b ) n — wherein R a and R b are independently selected from —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;

R 6 is selected from —H and —C 1 -C 8 alkyl;

each R 8 is independently selected from —H, —OH, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle and —O—(C 1 -C 8 alkyl);

R 9 is selected from —H and —C 1 -C 8 alkyl;

R 10 is selected from aryl group and —C 3 -C 8 heterocycle;

or a pharmaceutically acceptable salt thereof.

16. A compound having the formula:

wherein,

independently at each location:

R 2 is selected from H and —C 1 -C 8 alkyl;

R 4 is selected from —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle) wherein R 5 is selected from —H and -methyl; or R 4 and R 5 jointly have the formula —(CR a R b ) n — wherein R a and R b are independently selected from —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;

R 6 is selected from —H and —C 1 -C 8 alkyl;

each R 8 is independently selected from —H, —OH, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle and —O—(C 1 -C 8 alkyl);

R 9 is selected from —H and —C 1 -C 8 alkyl;

R 10 is selected from aryl group and —C 3 -C 8 heterocycle;

or a pharmaceutically acceptable salt thereof.

17. A compound having the formula:

wherein,

independently at each location:

R 2 is selected from —H and —C 1 -C 8 alkyl;

R 4 is selected from —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle) wherein R 5 is selected from —H and -methyl; or R 4 and R 5 jointly have the formula —(CR a R b ) n — wherein R a and R b are independently selected from —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;

R 6 is selected from —H and —C 1 -C 8 alkyl;

each R 8 is independently selected from —H, —OH, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle and —O—(C 1 -C 8 alkyl);

R 9 is selected from —H and —C 1 -C 8 alkyl;

R 10 is selected from aryl group and —C 3 -C 8 heterocycle;

or a pharmaceutically acceptable salt thereof.

18. A compound having the formula:

wherein,

independently at each location:

R 2 is selected from H and —C 1 -C 8 alkyl;

R 4 is selected from —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle) wherein R 5 is selected from —H and -methyl; or R 4 and R 5 jointly have the formula —(CR a R b ) n — wherein R a and R b are independently selected from —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;

R 6 is selected from —H and —C 1 -C 8 alkyl;

each R 8 is independently selected from —H, —OH, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle and —O—(C 1 -C 8 alkyl);

R 9 is selected from —H and —C 1 -C 8 alkyl;

R 10 is selected from aryl group and —C 3 -C 8 heterocycle;

or a pharmaceutically acceptable salt thereof.

19. A compound having the formula:

wherein,

independently at each location:

R 2 is selected from H and —C 1 -C 8 alkyl;

R 4 is selected from —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle) wherein R 5 is selected from —H and -methyl; or R 4 and R 5 jointly have the formula —(CR a R b ) n — wherein R a and R b are independently selected from —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;

R 6 is selected from —H and —C 1 -C 8 alkyl;

each R 8 is independently selected from —H, —OH, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle and —O—(C 1 -C 8 alkyl);

R 9 is selected from —H and —C 1 -C 8 alkyl;

R 10 is selected from aryl group and —C 3 -C 8 heterocycle;

or a pharmaceutically acceptable salt thereof.

20. A compound having the formula:

wherein,

independently at each location:

R 2 is selected from H and —C 1 -C 8 alkyl;

R 4 is selected from —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle) wherein R 5 is selected from —H and -methyl; or R 4 and R 5 jointly have the formula —(CR a R b ) n — wherein R a and R b are independently selected from —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;

R 6 is selected from —H and —C 1 -C 8 alkyl;

each R 8 is independently selected from —H, —OH, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle and —O—(C 1 -C 8 alkyl);

R 9 is selected from —H and —C 1 -C 8 alkyl;

R 10 is selected from aryl group and —C 3 -C 8 heterocycle;

or a pharmaceutically acceptable salt thereof.

21. The compound or a pharmaceutically acceptable salt of the compound of any one of claims 2 , 3 , 5 , 6 and 7 , 8 , 9 , 10 that is in isolated and purified form.

22. The compound or a pharmaceutically acceptable salt of the compound of any one of claims 13 , 11 , 12 , 14 , 15 , 16 , 17 , 18 , 19 , 20 and 1 that is in isolated and purified form.

Assignments (7)

CHANGE OF NAME Recorded Jan 11, 2021

From: SEATTLE GENETICS, INC.

To: SEAGEN INC.

Reel/Frame 054960/0348 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 17, 2006

From: EBENS, ALLEN J.; POLAKIS, PAUL; SLIWKOWSKI, MARK X.; SPENCER, SUSAN D.

To: GENENTECH, INC.

Reel/Frame 017270/0587 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 1, 2005

From: DORONINA, SVETLANA O.; SENTER, PETER D.; TOKI, BRIAN E.; KLINE, TONI BETH

To: SEATTLE GENETICS, INC.