Substituted pyrazino[1′,2′:1 ,5]pyrrolo[2,3-b]indole-1,4-diones for cancer treatment

Patent metadata

Field	Value
Publication number	US-10220099-B2
Application number	US-201615150786-A
Country	US
Kind code	B2
Filing date	May 10, 2016
Priority date	Dec 4, 2012
Publication date	Mar 5, 2019
Grant date	Mar 5, 2019

Abstract

The synthesis of various pyrazino[1′,2′:1,5]pyrrolo[2,3-b]-indole-1,4-dione analogs has been successfully implemented in the present application. From these efforts, compounds having the structure of Formula I-c:

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 1 , R 2 , R 4 -R 8 , R 3′ , R 6′ , and n are as defined herein, are provided. These biologically active derivatives have been further used to prepare cell-specific drug conjugates effective in treating various diseases including cancer.

First claim

The invention claimed is:

1. A compound having the structure of formula II:
M L D) s ] t    II

or a pharmaceutically acceptable salt thereof, wherein:
M is a cell-specific ligand unit;
each L is independently a linker unit;
each D independently has the structure of formula I-c or I-d,

or a pharmaceutically acceptable salt thereof, wherein:
each is independently a single bond or a double bond;
each R 1 is independently R, —C(O)R, —C(O)N(R) 2 , —S(O)R, —S(O) 2 R, —S(O) 2 OR, —C(R) 2 OR, or —S(O) 2 N(R) 2 ;
each R is independently hydrogen or an optionally substituted group selected from C 1-20 aliphatic, C 1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or
two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R 2 is independently R, —[C(R) 2 ] q —OR, —[C(R) 2 ] q —N(R) 2 , —[C(R) 2 ] q —SR, —[C(R) 2 ] q —OSi(R) 3 , —[C(R) 2 ] q —OC(O)R, —[C(R) 2 ] q —OC(O)OR, —[C(R) 2 ] q —OC(O)N(R) 2 , —[C(R) 2 ] q —OC(O)N(R)—SO 2 R or —[C(R) 2 ] q —OP(OR) 2 ; or
R 1 and R 2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R 1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur;
each q is independently 0, 1, 2, 3, or 4;
each R 3′ is independently R, or an electron-withdrawing group;
each R 4 is independently absent when is a double bond or is independently R or halogen;
each R 5 is independently absent when is a double bond or is independently hydrogen or an optionally substituted C 1-6 aliphatic group;
each of R 6 and R 6′ is independently R, halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —S(O) 2 R,

—S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, or —OSi(R) 3 ; or
R 6 and R 6′ are taken together to form ═O, ═C(R) 2 or ═NR;
each n is independently 0, 1, 2, 3, or 4;
each R 7 is independently R, halogen, —CN, —NO 2 , —OR, —OSi(R) 3 , —SR, —N(R) 2 , —S(O) 2 R,

—S(O) 2 OR, —S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —P(R) 2 , —P(OR) 2 , —P(O)(R) 2 , —P(O)(OR) 2 , —P(O)[N(R) 2 ] 2 , —B(R) 2 , —B(OR) 2 , or —Si(R) 3 ; or
two R 7 are taken together with their intervening atoms to form an optionally substituted 4-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R 8 is independently —(S) m —R x wherein m is 1, 2, or 3, and R x is R, —SR, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(S)R, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ;
each R 9 is independently —(S) p —R y wherein p is 1, 2, or 3, such that the sum of m and p is 2, 3, or 4, and R y is R, —SR, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(S)R, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ; or
R 8 and R 9 are taken together to form —S—, —(S) m —[C(R) 2 ] q —(S) p —, —(S) m —(S) p —, —(S) m —C(O)—(S) p —, —(S) m —C(S)—(S) p —, —(S) m —S(O)—(S) p —, or —(S) m —S(O) 2 —(S) p —;
s is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
t is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

2. The compound of claim 1 , wherein the compound has the structure of formula II-a:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound has the structure of formula II-b:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein s is 1.

5. The compound of claim 1 , wherein L is self-immolative.

6. The compound of claim 1 , wherein M is an antibody.

7. The compound of claim 1 , wherein R 3′ is R.

8. The compound of claim 1 , wherein R 3′ is an electron-withdrawing group.

9. The compound of claim 1 , wherein
R 3′ is —S(O) 2 R, —S(O) 2 —[C(R) 2 ] q —R, —S(O) 2 —[C(R) 2 ] q —B(OR) 2 , —S(O) 2 —[C(R) 2 ] q —Si(R) 3 , —S(O) 2 OR, —S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)—OR, —P(O)(R) 2 , —P(O)(OR) 2 , or —P(O)[N(R) 2 ] 2 .

10. The compound of claim 1 , wherein R 3′ is —SO 2 R.

11. The compound of claim 1 , wherein each R 4 is independently an optionally substituted group selected from phenyl, an 8-14 membered bicyclic or tricyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-14 membered bicyclic or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

12. The compound of claim 1 , wherein
R 8 is —(S) m —R x wherein m is 1, 2, or 3, and R x is —SR, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(S)R, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ; and
R 9 is —(S) p —R y wherein p is 1, 2, or 3, such that the sum of m and p is 2, 3, or 4, and R y is —SR, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(S)R, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ; or
R 8 and R 9 are taken together to form —S—, —(S) m —[C(R) 2 ] q —(S) p —, —(S) m —(S) p —, —(S) m —C(O)—(S) p —, —(S) m —C(S)—(S) p —, —(S) m —S(O)—(S) p —, or —(S) m —S(O) 2 —(S) p —.

13. The compound of claim 1 , wherein R 8 and R 9 are taken together to form —S—, —(S) m —C(R) 2 —(S) p —, —(S) m —(S) p —, —(S) m —C(O)—(S) p —, —(S) m —C(S)—(S) p —, —(S) m —S(O)—(S) p —, or —(S) m —S(O) 2 —(S) p —.

14. The compound of claim 1 , wherein:
R 8 is —(S) m —R x wherein m is 1 and R x is —SR or —C(O)R; and
R 9 is —(S) p —R y wherein p is 1 and R y is —SR or —C(O)R.

15. The compound of claim 1 , wherein R 8 and R 9 are taken together to form —(S) m —(S) p —, —S—C(O)—S—, or —S—C(S)—S—.

16. The compound of claim 1 , wherein:
each is independently a single bond;
each R 4 is independently R or halogen; and
each R 5 is independently hydrogen or an optionally substituted C 1-6 aliphatic group.

17. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. A method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

19. The method of claim 18 , wherein the cancer is lymphoma.

20. the method of claim 18 , wherein the cancer is cervical cancer, lung cancer, renal cancer, or breast cancer

Assignees

• Massachusetts Inst Technology
• Univ Illinois

Inventors

• Movassaghi Mohammad
• Kim Justin
• Hergenrother Paul J
• Morrison Karen
• Boyer Nicolas

Classifications

• C07D513/22

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

• C07K5/12

  Cyclic peptides {with only normal peptide bonds in the ring} · CPC title

• A61K47/48384 Primary

  Human Necessities · mapped topic

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• C07D487/14 Primary

  Ortho-condensed systems · CPC title