Pyrrolbenzodiazepines

• US 7,049,311 B1
• Filed: 08/27/1999
• Issued: 05/23/2006
• Est. Priority Date: 08/27/1998
• Status: Expired due to Term

• Current Assignee: MedImmune Ltd. (Astrazeneca PLC)
• Original Assignee: Spirogen Limited
• Inventors: Howard, Philip Wilson, Thurston, David Edwin
• Primary Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US09/763,767
• Time in Patent Office: 2,461 Days
• Field of Search: 514/220, 540/486, 540/496
• US Class Current: 514/220
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Compounds of formula (Ia) and (Ib) wherein A is CH₂, or a single bond; R₂ is selected from: R, OH, OR, CO₂H, CO₂R, COH, COR, SO₂R, CN; R₆, R₇ and R₉ are independently selected from H, R, OH, OR, halo, amino, NHR, nitro, Me₃Sn; and R₈ is selected from H, R, OH, OR, halo, amino, NHR, nitro, Me₃Sn, where R is as defined above, or the compound is a dimer with each monomer being the same or different and being of formula (Ia) or (Ib), where the R₈ groups of the monomers form together a bridge having the formula —X—R′—X— linking the monomers, where R′ is an alkylene chain containing from 3 to 12 carbon atoms, which chain may be interrupted by one or more hetero-atoms and/or aromatic rings and may contain one or more carbon—carbon double or triple bonds, and each X is independently selected from O, S, or N; except that in a compound of formula (Ia) when A is a single bond, then R₂ is not CH═CH(CONH₂) or CH═CH(CONMe₂). Other related compounds are also disclosed

Claims

1. A pyrrolobenzodiazepine compound of the formula Ia or Ib:

wherein;

(a) A is CH₂;

R₂ is selected from;

R, OH, OR, CO₂H, CO₂R, COH, COR, SO₂R, or CN;

R₆, R₇ and R₉ are independently selected from H, R, OH, OR, halo, amino, NHR, nitro, Me₃Sn;

where R is a lower alkyl group having 1 to 10 carbon atoms, or an aralkyl group of up to 12 carbon atoms, whereof the alkyl group optionally contains one or more carbon—

carbon double or triple bonds, which may form part of a conjugated system, or one or more carbonyl groups or one or more ether or thioether groups, or an aryl group of up to 12 carbon atoms; and

is optionally substituted by one or more halo, hydroxy, amino, or nitro groups;

and R₈ is selected from H, R, OH, OR, halo, amino, NHR, nitro, Me₃Sn, where R is as defined above;

or

(b) A is a single bond;

R₂ is an aryl group of up to 12 carbon atoms;

R₆, R₇ and R₉ are independently selected from H, R, OH, OR, halo, amino, NHR, nitro, Me₃Sn;

where R is a lower alkyl group having 1 to 10 carbon atoms, or an aralkyl group of up to 12 carbon atoms, whereof the alkyl group optionally contains one or more carbon—

carbon double or triple bonds, which may form part of a conjugated system, or one or more carbonyl groups or one or more ether or thioether groups, or an aryl group of up to 12 carbon atoms; and

is optionally substituted by one or more halo, hydroxy, amino, or nitro groups;

and R₈ is selected from H, R, OH, OR, halo, amino, NHR, nitro, Me₃Sn, where R is as defined above, or where the compound is a dimer with each monomer being the same or different and being of formula Ia or Ib, where the R₈ groups of the monomers form together a bridge having the formula —

X—

R1—

X—

linking the monomers, where R¹ is an alkylene chain containing from 3 to 12 carbon atoms, which chain may be interrupted by one or more hetero-atoms and/or aromatic rings and may contain one or more carbon—

carbon double or triple bonds, and each X is independently selected from O, S, or N;

or R₇ and R₈ together form a group —

O—

(CH₂)_p—

O—

, where p is 1 or 2;

or

(c) A is CH₂, or a single bond;

R₂ is selected from;

R, OH, OR, CO₂H, CO₂R, COH, COR, SO₂R, or CN,

R₆, R₇ and R₉ are independently selected from H, R, OH, OR, halo, amino, NHR, nitro, Me₃Sn;

where R is a lower alkyl group having 1 to 10 carbon atoms, or an aralkyl group of up to 12 carbon atoms, whereof the alkyl group optionally contains one or more carbon—

carbon double or triple bonds, which may form part of a conjugated system, or one or more carbonyl groups or one or more ether or thioether groups, or an aryl group of up to 12 carbon atoms; and

is optionally substituted by one or more halo, hydroxy, amino, or nitro groups; and

where the compound is a dimer with each monomer being the same or different and being of formula Ia or Ib, where the R₈ groups of the monomers form together a bridge having the formula —

X—

R¹—

X—

linking the monomers, where R¹ is an alkylene chain containing from 3 to 12 carbon atoms, which chain may be interrupted by one or more hetero-atoms and/or aromatic rings and may contain one or more carbon—

carbon double or triple bonds, and each X is independently selected from O, S, or N;

or R₇ and R₈ together form a group —

O—

(CH₂)_p—

O—

, where p is 1 or 2.

2. A compound according to claim 1, wherein A is CH₂.

3. A compound according to claim 2, wherein R₂ is CO₂H, CO₂R, or CH₂OH.

4. A compound according to claim 3, wherein R₂ is CO₂Me, CO₂^tBu, or CH₂OH.

5. A compound according to claim 1(c), wherein A is a single bond, and R₂ is an aryl group, or an alkyl or alkaryl group which contains at least one double bond which forms part of a conjugated system with a double bond of the pyrrolobenzodiazepine compound C-ring.

6. A compound according to claim 1 wherein R₆, R₇ and R₉ and, unless the compound is a dimer, R₈ are independently selected from H and OR.

7. A compound according to claim 6, wherein R₆, R₇ and R₉ and, unless the compound is a dimer, R₈ are independently selected from H, OMe and OCH₂Ph.

8. A compound according to claim 6, wherein R₇ and, unless the compound is a dimer, R₈ are OR, and R₆ and R₉ are H.

9. A compound according to claim 8, wherein R₇ and, unless the compound is a dimer, R₈ are independently either OMe or OCH₂Ph.

10. A compound according to claim 1 which is a dimer, wherein the dimer bridge is of the formula —

O—

(CH₂)_q—

O—

, where q is from 3 to 12.

33. A compound according to claim 1, claim 12, claim 24 or claim 29 wherein R is selected from a lower alkyl group having 1 to 10 carbon atoms, or an aralkyl group of up to 12 carbon atoms, or an aryl group of up to 12 carbon atoms, optionally substituted by one or more halo, hydroxy, amino, or nitro groups.

34. A compound according to claim 33, wherein R is selected from a lower alkyl group having 1 to 10 carbon atoms optionally substituted by one or more halo, hydroxy, amino, or nitro groups.

35. A compound according to claim 34, wherein R is an unsubstituted straight or branched chain alkyl having 1 to 10 carbon atoms.

36. A process for preparing a compound according to claim 1 comprising cyclizing a compound of formula

wherein A, R₂, R₆, R₇, R₈ and R₉ are as defined in claim 1, R₁₀ is a nitrogen protecting group and CPQ is a masked aldehyde;

to a compound of formula

wherein A, R₂, R₆, R₇, R₈, R₉ and R₁₀ are as defined above and converting the above compound to a compound according to claim 1.

40. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

44. A method of treating cancer comprising administering an effective amount of a compound according to claim 1 or claim 18 to a patient in need of such treatment wherein the cancer is selected from lung cancer, colon cancer, CNS cancer, melanoma, renal cancer, breast cancer and ovarian cancer.

45. The method of claim 44 wherein the compound is selected from the group consisting of

11. A compound consisting of:

12. A compound of formula II:

wherein;

R₂ is O;

R₆, R₇ and R₉ are independently selected from H, R, OH, OR, halo, amino, NHR, nitro, Me₃Sn;

where R is a lower alkyl group having 1 to 10 carbon atoms, or an aralkyl group of up to 12 carbon atoms, whereof the alkyl group optionally contains one or more carbon—

carbon double or triple bonds, which may form part of a conjugated system, or one or more carbonyl groups or one or more ether or thioether groups, or an aryl group of up to 12 carbon atoms; and

is optionally substituted by one or more halo, hydroxy, amino, or nitro groups;

and where the compound is a dimer with each monomer being the same or different and being of formula II, where the R₈ groups of the monomers form together a bridge having the formula —

X—

R¹—

X—

linking the monomers, where R¹ is an alkylene chain containing from 3 to 12 carbon atoms, which chain may be interrupted by one or more hetero-atoms and/or aromatic rings and may contain one or more carbon—

carbon double or triple bonds, and each X is independently selected from O, S, or N.

13. A compound according to claim 12, wherein R₆, R₇ and R₉ are independently selected from H, OR or a halogen atom.

14. A compound according to claim 13, wherein R₆, R₇ and R₉ are independently selected from H, OMe, OCH₂Ph, and I.

15. A compound according to claim 13, wherein R₇ is OR or a halogen and R₆ and R₉ are H.

16. A compound according to claim 15, wherein R₇ is selected from OMe, OCH₂Ph or I.

17. A compound according to claim 12, wherein the dimer bridge is of the formula —

O—

(CH₂)_q—

O—

, where q is from 3 to 12.

37. A process for preparing a compound according to claim 12 comprising cyclizing a compound of formula

wherein R′ ₂, R₆, R₇, R₈ and R₉ are as defined in claim 13, R₁₀ is a nitrogen protecting group and CPQ is a masked aldehyde;

to a compound of the formula

wherein R′

₂, R₆, R₇, R₈, R₉ and R₁₀ are as defined above, and converting the above compound to a compound according to claim 12.

41. A composition comprising a compound according to claim 12 and a pharmaceutically acceptable carrier or diluent.

18. A compound of formula II:

wherein;

R′

₂ is CH₂;

R₆, R₇ and R₉ are independently selected from H, R, OH, OR, halo, amino, NHR, nitro, Me₃Sn;

where R is lower alkyl group having 1 to 10 carbon atoms, or an aralkyl group of up to 12 carbon atoms, whereof the alkyl group optionally contains one or more carbon—

carbon double or triple bonds, which may form part of a conjugated system, or an aryl group of up to 12 carbon atoms; and

is optionally substituted by one or more halo, hydroxy, amino, or nitro groups, and optionally containing one or more carbonyl groups or one or more ether or thioether groups;

and R₈ is selected from H, R, OH, OR, halo, amino, NHR, nitro, Me₃Sn, where R is as defined above or the compound is a dimer with each monomer being the same or different and being of formula II, where the R₈ groups of the monomers form together a bridge having the formula —

X—

R¹—

X—

linking the monomers, where R¹ is an alkylene chain containing from 3 to 12 carbon atoms, which chain may be interrupted by one or more hetero-atoms and/or aromatic rings and may contain one or more carbon—

carbon double or triple bonds, and each X is independently selected from O, S, or N.

19. A compound according to claim 18, wherein R₆, R₇ and R₉ and, unless the compound is a dimer, R₈ are independently selected from H, OR or a halogen atom.

20. A compound according to claim 19 wherein R₆, R₇ and R₉ and, unless the compound is a dimer, R₈ are independently selected from H, OMe, OCH₂Ph, and 1.

21. A compound according to claim 19, wherein R₇ and, unless the compound is a dimer, R₈ are independently OR or a halogen atom and R₆ and R₉ are H.

22. A compound according to claim 21, wherein R₇ and, unless the compound is a dimer, R₈ are independently selected from OMe, OCH₂Ph or I.

23. A compound according to claim 18 which is a dimer, wherein the dimer bridge is of the formula —

O—

(CH₂)_q—

O—

, where q is from 3 to 12.

38. A process for preparing a compound according to claim 24 comprising cyclizing a compound of formula

wherein R₆, R₇, R₈, and R₉ are as defined in claim 20, R₁₀ is a nitrogen protecting group and CPQ is a masked aldehyde;

to a compound of formula

wherein R₆, R₇, R₈, R₉ and R₁₀ are as defined above, and converting the above compound to a compound according to claim 24.

24. A compound of the formula III:

wherein;

R₆, R₇ and R₉ are independently selected from H, R, OH, OR, halo, amino, NHR, nitro, Me₃Sn;

where R is a lower alkyl group having 1 to 10 carbon atoms, or an aralkyl group of up to 12 carbon atoms, whereof the alkyl group optionally contains one or more carbon—

carbon double or triple bonds, which may form part of a conjugated system, or one or more carbonyl groups, or one or more ether or thioether groups, or an aryl group of up to 12 carbon atoms; and

is optionally substituted by one or more halo, hydroxy, amino, or nitro groups;

and R₈ is amino.

25. A compound according to claim 24, wherein only one of R₆, R₇ and R₉ is H.

26. A compound according to claim 24, wherein at least one of R₆, R₇ and R₉ is an aryl group of up to 12 carbon atoms, which is optionally substituted by one or more halo, hydroxy, amino, or nitro groups.

27. A compound according to claim 26, wherein at least one of R₆, R₇ and R₉, is a phenyl group, optionally substituted by one or more nitro groups.

28. A compound according to claim 27, wherein at least one of R₆, R₇ and R₉, is selected from:

Ph, m-NO₂-Ph and p-NO₂-Ph.

42. A composition comprising a compound according to claim 24 and a pharmaceutically acceptable carrier or diluent.

47. A method of treating cancer comprising administering an effective amount of a compound according to claim 24 to a patient in need of such a treatment wherein the cancer is selected from lung cancer, colon cancer, CNS cancer, melanoma, renal cancer and breast cancer.

29. A compound of formula IV:

wherein;

R₆, R₇ and R₉ are independently selected from H, R, OH, OR, halo, amino, NHR, nitro, Me₃Sn;

where R is a lower alkyl group having 1 to 10 carbon atoms, or an aralkyl group of up to 12 carbon atoms, whereof the alkyl group optionally contains one or more carbon—

carbon double or triple bonds, which may form part of a conjugated system, or one or more carbonyl groups, or one or more ether or thioether groups, or an aryl group of up to 12 carbon atoms; and

is optionally substituted by one or more halo, hydroxy, amino, or nitro groups;

R₈′ and

R₈″

are either independently selected from H, R or together form a cyclic amine; and

n is from 1 to 7.

30. A compound according to claim 29, wherein R₆ and R₉ are selected from H and OR.

31. A compound according to claim 30, wherein R₆ and R₉ are selected from OMe, OEt and OBn.

32. A compound according to claim 30, wherein n is 1 to 3.

39. A process for preparing a compound according to claim 29 comprising cyclizing a compound of formula

wherein R₆, R₇, R₈′ , R₈″

, and R₉ are as defined in claim 29, R₁₀ is a nitrogen protecting group and CPQ is a masked aldehyde;

to a compound of formula

wherein R₆, R₇, R₈′

, R₈″

, R₉ and R₁₀ are as defined above, and converting the above compound to a compound according to claim 29.

43. A composition comprising a compound according to claim 29 and a pharmaceutically acceptable carrier or diluent.

49. A method of treating cancer comprising administering an effective amount of a compound according to claim 29 to a patient in need of such treatment wherein the cancer is selected from lung cancer, colon cancer, CNS cancer, melanoma, renal cancer and ovarian cancer.

50. The method of claim 49 wherein the compound is selected from the group consisting of

46. A method of treating cancer comprising administering an effective amount of a compound wherein the compound is selected from the group consisting of

to a patient in need of such treatment and wherein the cancer is selected from lung cancer, colon cancer, CNS cancer, melanoma, renal cancer, breast cancer and ovarian cancer.

48. A method of treating cancer comprising administering an effective amount of a compound of the formula

to a patient in need of such treatment wherein the cancer is selected from lung cancer, colon cancer, CNS cancer, melanoma, renal cancer, and breast cancer.