Peptide conjugates of cytotoxins as therapeutics
The present invention relates to peptide conjugates of cytotoxins such as topoisomerase I inhibitors which are useful for the treatment of diseases such as cancer.
1. A compound of Formula (I):
R 8 -Q-R 7 (I)
or a pharmaceutically acceptable salt thereof, wherein:
R 7 is a peptide;
R 8 is:
Q is:
R 1 and R 3 together with the carbon atoms to which they are attached form a C 3-14 cycloalkyl group or 4-14 membered heterocycloalkyl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C 1-4 alkyl, halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 ,
R 2 and R 4 are each independently selected from H, C 1-4 alkyl, C 1-4 alkenyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 NR d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 , wherein said C 1-4 alkyl, C 1-4 alkenyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 ; and
R a1 , R b1 , R c1 , and R d1 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OH, CN, NO 2 , and CO 2 CH 3 ; wherein said C 1-6 alkyl and C 2-6 alkenyl are each optionally substituted with OH, CN, NO 2 , or CO 2 CH 3 .
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is a peptide capable of selectively delivering R 8 Q- across a cell membrane having an acidic or hypoxic mantle having a pH less than about 6.0.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is a peptide comprising at least one of the following sequences:
ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1; Pv1);
AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO: 2; Pv2);
ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO: 3; Pv3);
Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG (SEQ ID NO: 4; Pv4); and
AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC (SEQ ID No. 5; Pv5); and wherein R 7 is attached to Q through a cysteine residue of R 7 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is a peptide comprising at least one of the following sequences:
ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1; Pv1),
AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO: 2; Pv2), and
ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO: 3; Pv3), and wherein R 7 is attached to Q through a cysteine residue of R 7 .
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is a peptide comprising the sequence:
ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1; Pv1).
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is a peptide comprising the sequence:
AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO: 2; Pv2).
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 3 together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl, cycloheptyl, 1,2,3,4-tetrahydronaphthyl, tetrahydrofuranyl, or tetrahydropyranyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 3 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 3 together with the carbon atom to which they are attached form a cyclohexyl group.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is:
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 4 are each H.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from:
wherein Pv2 is a peptide comprising the sequence:
AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO: 2).
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from:
wherein Pv1 is a peptide comprising the sequence:
ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1).
14. A pharmaceutical composition that comprises a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is:
wherein Pv1 is a peptide comprising the sequence:
ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1).
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is:
wherein Pv1 is a peptide comprising the sequence:
ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1).