Prodrugs of CC-A1065 analogs

• US 8,012,978 B2
• Filed: 09/04/2008
• Issued: 09/06/2011
• Est. Priority Date: 03/07/2006
• Status: Expired due to Fees

• Current Assignee: ImmunoGen Incorporated
• Original Assignee: ImmunoGen Incorporated
• Inventors: Zhao, Robert, Chari, Ravi V. J.
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US12/204,082
• Publication Number:
  US 20090028821A1
• Time in Patent Office: 1,097 Days
• Field of Search: 514/252.2, 514/411, 548/414, 548/427
• US Class Current: 514/252.2
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/04 Amoebicides
• CPC Class Codes: A61P 33/12 Schistosomicides
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 209/60 Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention provides prodrugs of analogs of the anti-tumor antibiotic CC-1065 having a cleavable protective group containing a sulfonic acid containing phenyl carbamate, in which the protecting group confers enhanced water solubility upon the prodrug, and in which the prodrug also has a moiety, such as a sulfide or a disulfide, that can conjugate to a cell binding reagent such as an antibody, and for the therapeutic use of such prodrug and conjugates, and for processes for preparing such prodrugs and conjugates.

Claims

1. A prodrug of the following formula:

2. The prodrug according to claim 1, wherein R₉═

H.

3. The prodrug according to claim 1, wherein one of R₁₀, R₁₁, R₁₂, and R₁₃═

—

X—

SO₃⁻

M⁺ and the others are H.

4. The prodrug according to claim 2, wherein one of R₁₀, R₁₁, R₁₂, and R₁₃═

—

X—

SO₃⁻

M⁺ and the others are H.

5. The prodrug according to claim 1, wherein R′

, R₁, R₂ and R₆are hydrogen and R is a linker.

6. The prodrug according to claim 1, wherein said linker has a thiol, sulfide or a disulfide bond containing substituent.

7. The prodrug according to claim 1, wherein said linker has a polyethylene glycol of the formula —

(OCH₂ CH₂)_n—

, wherein n is an integer from 1 to 2000.

8. The prodrug according to claim 1, wherein said linker group is of formula:

-G-D-(Z)p-S—

Z′

where

G is a single or double bond, —

O—

, —

S—

or —

NT-;

D is a single bond or -E-, -E-NT-, -E-NT-F—

, -E-O—

, -E-O—

F—

, -E-NT-CO—

, -E-NT-CO—

F—

, -E-CO—

, —

CO-E-, -E-CO—

F, -E-S—

, -E-S—

F—

, -E-NT-C—

S—

, -E-NT-CS—

F—

;

where T is H or a C₁-C₆ branched or linear alkyl;

where E and F are the same or different and are independently chosen from linear or branched —

(OCH₂CH₂)_ialkyl(OCH₂CH₂)_j—

, alkyl(OCH₂CH₂)_ialkyl-, —

(OCH₂CH₂)_i—

, —

(OCH₂CH₂)_icycloalkyl(OCH₂CH₂)_j—

, —

(OCH₂CH₂)_iheterocyclic(OCH₂CH₂)_j—

, —

(OCH₂CH₂)_iaryl(OCH₂CH₂)_j—

, —

(OCH₂CH₂)_iheteroaryl(OCH₂CH₂)_j—

, -alkyl-(OCH₂CH₂)_ialkyl(OCH₂CH₂)_j—

, -alkyl-(OCH₂CH₂)_i, -alkyl-(OCH₂CH₂)_icycloalkyl(OCH₂CH₂)_j—

, -alkyl(OCH₂CH₂)_iheterocyclic(OCH₂CH₂)_j—

, -alkyl-(OCH₂CH₂)_iaryl(OCH₂CH₂)_j—

, -alkyl(OCH₂CH₂)_iheteroaryl(OCH₂CH₂)_j—

, cycloalkyl-alkyl-, -alkyl-, -cycloalkyl-, -heterocyclic-alkyl-, -alkyl-heterocyclic-, -alkyl-aryl-, -aryl-alkyl-, -alkyl-heteroaryl- , -heteroaryl-alkyl-;

where i and j, identical or different are integers and independently chosen from 0, 1 to 2000;

Z is linear or branched alkyl;

p is 0 or 1; and

Z′

represents H, a thiol protecting group such as COR, R₂₀ or SR₂₀, wherein R₂₀ represents H, methyl, alkyl, optionally substituted cycloalkyl, aryl, heteroaryl or heterocyclic.

9. The prodrug according to claim 8, wherein G is a single bond or —

NT-.

10. The prodrug according to claim 8, wherein G is —

NT-.

11. The prodrug according to claim 8, wherein D is —

CO-E-.

12. The prodrug according to claim 9, wherein D is —

CO-E-.

13. The prodrug according to claim 10, wherein D is —

CO-E-.

14. The prodrug according to claim 8 wherein E is a linear or branched alkyl.

15. The prodrug according to claim 9 wherein E is a linear or branched alkyl.

16. The prodrug according to claim 10 wherein E is a linear or branched alkyl.

17. The prodrug according to claim 12 wherein E is a linear or branched alkyl.

18. The prodrug according to claim 8, wherein p is 0.

19. The prodrug according to claim 8, wherein Z′

is H or SR₂₀, wherein R₂₀ represents alkyl or heteroaryl.

20. The prodrug according to claim 18, wherein Z′

is H or SR₂₀, wherein R₂₀ represents alkyl or heteroaryl.

21. The prodrug according to claim 1, wherein said linker is selected from the group consisting of (CH₂)_pNHCO(CH₂)_mSZ, (CH₂)_pNHCOC₆H₄(CH₂)_mSZ, (CH₂)_pO(CH₂)_mSZ, (CH₂)_pNHCO(CH₂)_m(OCH₂CH₂)_nSZ, (CH₂)_pNHCOC₆H₄(CH₂)_m(OCH₂CH₂)_nSZ, (CH₂)_pO(CH₂)_m(OCH₂CH₂)_nSZ, (CH₂)_pNHCO(CH₂)_mCH(Me)SZ, (CH₂)_pNHCOC₆H₄(CH₂)_mCH(Me)SZ, (CH₂)_pO(CH₂)_mCH(Me)SZ, (CH₂)_pNHCO(CH₂)_m(OCH₂CH₂)_nCH(Me)SZ, (CH₂)_pNHCOC₆H₄(CH₂)_m(OCH₂CH₂)_nCH(Me)SZ, (CH₂)_pO(CH₂)_m(OCH₂CH₂)_nCH(Me)SZ, (CH₂)_pNHCO(CH₂)_mC(Me)₂SZ, (CH₂)_pNHCOC₆H₄(CH₂)_mC(Me)₂SZ, (CH₂)_pO(CH₂)_mC(Me)₂SZ, (CH₂)_pNHCO(CH₂)_m(OCH₂CH₂)_nC(Me)₂SZ, (CH₂)_pNHCOC₆H₄(CH₂)_m(OCH₂CH₂)_nC(Me)₂SZ, (CH₂)_pO(CH₂)_m(OCH₂CH₂)_nC(Me₂)SZ, (CH₂)_pOC₆H₄(CH₂)_mSZ, (CH₂)_pOC₆H₄(CH₂)_mCH(Me)SZ, (CH₂)_pOC₆H₄(CH₂)_m(OCH₂CH₂)_nCHMeSZ, (CH₂)_pOC₆H₄(CH₂)_mCMe₂SZ and (CH₂)_pOC₆H₄(CH₂)_m(OCH₂CH₂)_nC(Me)₂SZ, wherein:

Z represents H, or a thiol protecting group;

m represents an integer of 0 to 10;

n represents an integer of 0 to 2000; and

p represents an integer of 0 to 10.

22. The prodrug according to claim 21, wherein said linker is selected from the group consisting of (CH₂)_pNHCO(CH₂)₂SH, (CH₂)_pNHCO(CH₂)₂C(Me)₂SH, (CH₂)_pNHCO(CH₂)₂SSCH₃, (CH₂)_pNHCO(CH₂)₂(OCH₂CH₂)_nSH, (CH₂)_pNHCO (CH₂)₂(OCH₂CH₂)_nC(Me)₂SSCH₃ and (CH₂)_pNHCO(CH₂)₂(OCH₂CH₂)_nSSMe.

24. A conjugated of a cell binding agent linked to a prodrug according to claim 1, wherein said cell binding agents is selected from the group consisting of antibodies and fragments thereof, interferons, lymphokines, vitamins, hormones and growth factors.

25. The conjugate according to claim 24, wherein said cell binding agents are antibodies or fragments thereof.

26. The conjugate according to claim 24, wherein the linking group comprises the linker linked to a function reactive towards thiol, sulfide or disulfide.

27. The conjugate according to claim 25, wherein the linking group comprises the linker linked to a function reactive towards thiol, sulfide or disulfide.

28. A pharmaceutical composition comprising the conjugate according to claim 24 and a pharmaceutically acceptable carrier.

29. A pharmaceutical composition comprising the conjugate according to claim 25 and a pharmaceutically acceptable carrier.

30. A process for the preparation of the prodrug according to claim 1, comprising the step of protecting the phenolic group of the alkylating portion of the following compound,

31. The process of preparation according to claim 30, which further comprises the step of hydrolyzing the obtained product.

32. The process according to claim 30, which further comprises the step of isolating the desired product.

33. The process according to claim 31, which further comprises the step of isolating the desired product.

23. A prodrug which is

(S)-3-((1-(chloromethyl)-3-(5-(3-mercaptopropanamido)-1H-indole-2-carbonyl)-2,3-dihydro-1H-benzo[e]indol-5-yloxy)carbonylamino)benzenesulfonic acid;

or

(S)-3-((1-(chloromethyl)-3-(5-(3-(methyldisulfanyl)propanamido)-1H-indole-2-carbonyl)-2,3-dihydro-1H-benzo[e]indol-5-yloxy)carbonylamino)benzenesulfonic acid;

or

an optical isomer, racemate, diastereomer or enantiomer of such prodrug, or a pharmaceutically acceptable salt, of such prodrug, optical isomer, racemate, diastereomer or enantiomer.