Camptothecin derivatives

US 6,350,756 B1
Filed: 03/01/2001
Issued: 02/26/2002
Est. Priority Date: 01/18/2001
Status: Expired

First Claim

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1. A compound of the formula wherein R is R₁—

O—

(CH₂)_m—

, m is an integer of 1-10 and R₁isphenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, formyl, lower alkyl carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperazino, lower alkoxycarbonyl, and lower alkylcarbonylamino;

a fused, 2-, 3-, or 4-ring heterocyclic system optionally substituted with one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino;

1- or 2-naphthyl optionally substituted with from one to four substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino;

a 5 or 6 membered heterocyclic ring containing one or two nitrogen atoms, which ring is optionally substituted with one or two substituents selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino;

R₂is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is defined hereinbefore), cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, tri lower alkylsilyl, lower alkylcarbonyloxy, lower alkylcarbonylamino, lower alkylcarbonyloxy methyl, substituted vinyl, 1-hydroxy-2-nitroethyl, alkoxycarbonylethyl, aminocarbonyl, mono- or di-alkylcarbonyl, alkylcarbonyloxymethyl, benzoylmethyl, benzylcarbonyloxymethyl, or mono- or di lower alkoxymethyl;

R₃is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is defined hereinbefore) cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, CH₂NR₇R₈(where each of R₇and R₈is independently H—

, alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or dialkylamino lower alkyl, or R₇and R₈taken together with —

N—

represent a cyclic amino-), CH₂R₉(where R₈is lower alkoxy, CN, amino lower alkoxy, mono- or di-lower alkylamino lower alkoxy, lower alkylthio, amino lower alkylthio, or mono- or di-lower alkylamino lower alkylthio), or NR₁₀R₁₁(where each of R₁₀and R₁₁is independently hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or di-lower alkyl, or R₁₀and R₁₁taken together with —

N—

represent a cyclic amino), dialkylamino alkyl, lower alkylcarbonyloxy, or lower alkylcarbonylamino; and

R₄is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is defined hereinbefore) cyano, nitro, amino, amino lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, or lower alkylcarbonylamino, or R₄together with R₅is methylenedioxy;

R₅is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is defined hereinbefore) cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, or lower alkylcarbonylamino; and

R₆is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is defined hereinbefore) cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, or lower alkylcarbonylamino.

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Abstract

(20S) esters of camptothecin analogs are provided. The compounds are (20S) esters of an oxyalkanoic acid and camptothecin, which is optionally substituted at the 7, 9, 10, 11, and 12 positions of the camptothecin ring. The compounds are useful for treating cancer.

Citations

54 Claims

1. A compound of the formula wherein R is R₁—
- O—
  
  (CH₂)_m—
  
  , m is an integer of 1-10 and R₁isphenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, formyl, lower alkyl carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperazino, lower alkoxycarbonyl, and lower alkylcarbonylamino;
  
  a fused, 2-, 3-, or 4-ring heterocyclic system optionally substituted with one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino;
  
  1- or 2-naphthyl optionally substituted with from one to four substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino;
  
  a 5 or 6 membered heterocyclic ring containing one or two nitrogen atoms, which ring is optionally substituted with one or two substituents selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino;
  
  R₂is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is defined hereinbefore), cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, tri lower alkylsilyl, lower alkylcarbonyloxy, lower alkylcarbonylamino, lower alkylcarbonyloxy methyl, substituted vinyl, 1-hydroxy-2-nitroethyl, alkoxycarbonylethyl, aminocarbonyl, mono- or di-alkylcarbonyl, alkylcarbonyloxymethyl, benzoylmethyl, benzylcarbonyloxymethyl, or mono- or di lower alkoxymethyl;
  
  R₃is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is defined hereinbefore) cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, CH₂NR₇R₈(where each of R₇and R₈is independently H—
  
  , alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or dialkylamino lower alkyl, or R₇and R₈taken together with —
  
  N—
  
  represent a cyclic amino-), CH₂R₉(where R₈is lower alkoxy, CN, amino lower alkoxy, mono- or di-lower alkylamino lower alkoxy, lower alkylthio, amino lower alkylthio, or mono- or di-lower alkylamino lower alkylthio), or NR₁₀R₁₁(where each of R₁₀and R₁₁is independently hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or di-lower alkyl, or R₁₀and R₁₁taken together with —
  
  N—
  
  represent a cyclic amino), dialkylamino alkyl, lower alkylcarbonyloxy, or lower alkylcarbonylamino; and
  
  R₄is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is defined hereinbefore) cyano, nitro, amino, amino lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, or lower alkylcarbonylamino, or R₄together with R₅is methylenedioxy;
  
  R₅is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is defined hereinbefore) cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, or lower alkylcarbonylamino; and
  
  R₆is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is defined hereinbefore) cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, or lower alkylcarbonylamino.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54)
- - 2. The compound of claim 1 wherein m is 1, each of R₂through R₆is H, and R₁is phenyl optionally substituted with one to three substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, and benzyloxy.
  - 3. The compound of claim 2 wherein R₁is phenyl optionally substituted with one to three substituents independently selected from lower alkyl, halo, halogenated lower alkoxy, and lower alkoxy.
  - 4. The compound of claim 3 wherein R₁is phenyl optionally substituted with one to three halo substituents.
  - 5. The compound of claim 4 wherein R₁is phenyl.
  - 6. The compound of claim 4 wherein R₁is 4-halophenyl.
  - 7. The compound of claim 4 wherein R₁is 3-chlorophenyl or 2-chlorophenyl.
  - 8. The compound of claim 4 wherein R₁is 2,4-dichlorophenyl.
  - 9. The compound of claim 4 wherein R₁is 4-fluorophenyl, 4-bromophenyl, or 4-iodophenyl.
  - 10. The compound of claim 4 wherein R₁is 2,3-dichlorophenyl.
  - 11. The compound of claim 4 wherein R₁is 2,3dicoro-4-fluorophenyl.
  - 12. The compound of claim 4 wherein R₁is 2-bromo-4-chlorophenyl.
  - 13. The compound of claim 4 wherein R₁is 3-chloro-4-fluorophenyl.
  - 14. The compound of claim 4 wherein R₁is 2,3-difluoro-5-bromophenyl.
  - 15. The compound of claim 4 wherein R₁is 2-bromo-4-fluorophenyl.
  - 16. The compound of claim 3 wherein R₁is 3-bromomethylphenyl.
  - 17. The compound of claim 2 wherein R₁is 3,5-dimothyl-4-chlorophenyl;
    - 2,5-dibromo-4-cyanophenyl;
      
      4-benzyloxyphenyl;
      
      4-trifluoromethoxyphenyl;
      
      or 4-hydroxycarbonylphenyl.
  - 18. The compound of claim 3 wherein R₁is phenyl substituted with one or two lower alkyl substituents.
  - 19. The compound of claim 18, wherein R₁is 4-alkyl-substituted phenyl.
  - 20. The compound of claim 18, wherein R₁is 2,4-dialkyl-substituted phenyl.
  - 21. The compound of claim 2, wherein R₁is monoalkoxy-substituted phenyl.
  - 22. The compound of claim 2, wherein R₁is 3,4-methylenedioxyphenyl.
  - 23. The compound of claim 1, wherein m is 1, each of R₂through R₆is H, and R₁is a fused, 2-ring heterocyclic system.
  - 24. The compound of claim 23, wherein R₁is represented by the formulas
  - 25. The compound of claim 1, wherein m is 1, each of R₂through R₆is H, and R₁is 1- or 2-naphthyl optionally substituted with from one to four substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy and lower alkylcarbonylamino.
  - 26. The compound of claim 25, wherein R₁is 2-naphthyl.
  - 27. The compound of claim 1, wherein m is 1, each of R₂through R₆is H, and R₁is
  - 29. The compound of claim 1, wherein m is 1, each of R₂through is H, and R₁is 4-nitrophenyl, 2-nitrophenyl, or 3-trifluoromethyl-4-nitrophenyl.
  - 30. The compound of claim 1, wherein m is an integer of 2-4, each of R₂through R₆is H, and R₁is phenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, carbonyl, hydroxycarbonyl, lower alkoxycarbonyl, benzyloxy, lower alkylcarbonyloxy and lower alkylcarbonylamnino.
  - 31. The compound of claim 1, wherein R₆is hydrogen.
  - 32. The compound of claim 31, wherein R₄and R₅together are methylenedioxy.
  - 33. The compound of claim 1, wherein R₂is hydrogen.
  - 34. The compound of claim 33, where R₃is nitro, amino, methyl, chloro, cyano, acetoxy, or acetylamino.
  - 35. The compound of claim 31, wherein R₅is hydrogen.
  - 36. The compound of claim 35, wherein R₃is hydrogen;
    - R₂is (3-chloro-n-propyl)dimethylsilyl, tert-butyldimethylsilyl, acetoxymethyl, cyano, formylethenyl, ethoxycarbonyl-ethenyl, cyanoethenyl, 2,2-dicyanoethenyl, (2-cyano-2-ethoxycarbony)ethenyl, ethoxycarbonyethyl, methyl, ethyl, or n-propyl; and
      
      R₄is hydroxy, acetoxy, amino, nitro, cyano, chloro, bromo, fluoro, lower alkyl, higher alkyl, lower alkoxy, carbamoyloxy, or formyl.
  - 37. The compound of claim 36, wherein R₂is ethyl and R₄is carbamoyloxy.
  - 38. The compound of claim 37, wherein carbamoyloxy is 1-piperazinylcarbonyloxy, 4(-i-propylaminocarbonylmethyl)-1-piperazinyl-carbonyloxy, or [4-(1-piperidino)-1-piperidino]-carbonyloxy.
  - 39. The compound of claim 31, wherein R₂and R₅are hydrogen.
  - 40. The compound of claim 39, wherein R₃is amino, nitro, cyano, halo, OH, lower alkylamino, di-lower alkylamino, lower alkyl, lower alkoxy, 1-piperidino, 1-mopholino, aminomethyl, lower alkylaminomethyl, cycloalkylaminomethyl, di-lower alkylaminomethyl, cyclic aminomethyl, acetoxy, acetylamino, lower alkoxymethyl, omega-hydroxy lower alkylaminomethyl, cyanomethyl, and R₄is hydroxy, acetoxy, cyano, nitro, amino, halo, formyl, lower alkoxy, carbamoyloxy.
  - 41. The compound of claim 31, wherein each of R₂, R₃, and R₅is hydrogen and R₄is —
    - OC(O)Alkyl_1-20.
  - 42. The compound of claim 1, wherein m is an integer of 1-5.
  - 43. The compound of claim 1, wherein m is 1.
  - 44. The compound of claim 1, wherein m is 1;
    - each of R₂, R₃, R₅, and R₆is hydrogen; and
      
      R4 is R₁—
      
      OCH₂C(O)—
      
      .
  - 45. A pharmaceutical composition useful for treating cancer in a warm-blooded animal, which composition comprises compound as defined in claim 1 in combination with a pharmaceutically acceptable excipient.
  - 46. The pharmaceutical composition of claim 45, suitable for oral administration.
  - 47. The pharmaceutical composition of claim 45 suitable for IV administration.
  - 48. The pharmaceutical composition of claim 45 suitable for IM administration.
  - 49. A method for treating cancer in a warm-blooded animal, which method comprises administering a therapeutically effective amount of a compound as defined in claim 1.
  - 50. The method of claim 49, wherein the compound is administered orally.
  - 51. The method of claim 49, wherein the compound is administered IV.
  - 52. The method of claim 49, wherein the compound is administered parenterally.
  - 53. A process of preparing a compound of claim 1, which comprises reacting
54. The process of claim 53 wherein the reacting takes place in the presence of the coupling agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the catalytic agent 4-(dimethylamino)pyridine.

28. The compound of cl;
- aim 1, wherein m is 1, each or R₂through R₆is H, and R₁is 4-formylphenyl.

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Current Assignee
Catholic Healthcare West (CommonSpirit Health (Illinois)), Sutter West Bay Hospitals
Original Assignee
California Pacific Medical Center (Sutter Health)
Inventors
Yang, Li-Xi, Wang, Huijuan, Pan, Xiandao
Primary Examiner(s)
Dentz, Bernard

Application Number

US09/797,769
Time in Patent Office

362 Days
Field of Search

546/41, 546/48, 514/283, 514/279, 544/361
US Class Current

514/283
CPC Class Codes

A61K 31/4745   condensed with ring systems...

A61P 35/00   Antineoplastic agents

C07D 491/22   in which the condensed syst...

Camptothecin derivatives

First Claim

7 Assignments

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Abstract

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54 Claims

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Camptothecin derivatives

First Claim

7 Assignments

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Abstract

Citations

54 Claims

Specification

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