Nitrogen-based homo-camptothecin derivatives
View Patent ↗(20) esters of camptothecin analogs are provided. The compounds are (20) esters of an aminoalkanoic acid or an imidoalkanoic acid and homocamptothecin, which is optionally substituted at the 7, 9, 10, 11, and 12 positions of the homocamptothecin ring. The compounds are useful for treating cancer.
1. A compound of the formula
wherein R is R a R b N—(CH 2 ) m ; m is an integer from 1-10; and
R 2 is 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 alkylcarbonyloxymethyl, substituted vinyl, 1-hydroxy-2-nitroethyl, alkoxycarbonylethyl, aminocarbonyl, alkylcarbonyl, alkylcarbonyloxymethyl, benzoylmethyl, benzylcarbonyloxymethyl, or mono- or di lower alkoxymethyl;
R 3 is 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, CH 2 NR 7 R 8 (where each of R 7 and R 8 is independently H—, alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or dialkylamino lower alkyl, or R 7 and R 8 taken together with —N— represent a cyclic amino-), CH 2 R 9 (where R 9 is 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 NR 10 R 11 (where each of R 10 and R 11 is independently hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or di-lower alkyl, or R 10 and R 11 taken together with —N— represent a cyclic amino), dialkylamino alkyl, lower alkylcarbonyloxy, or lower alkylcarbonylamino;
R 4 is 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 R 4 together with R 5 is methylenedioxy or ethylenedioxy;
R 5 is 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, or together with R 4 is methylenedioxy or ethylenedioxy;
R 6 is 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
R 12 and R 13 are independently hydrogen, lower alkyl, cyano, hydroxycarbonyl, lower alkoxycarbonyl, cycloalkyl, alkylcarbonylamino, 1-napthyl, 2-napthyl or phenyl.
2. The compound of claim 1 , wherein each R 2 through R 6 , R 12 , and R 13 is H, m is 2, and R a R b N—(CH 2 ) m is a cyclic imide ring.
3. The compound of claim 1 , wherein each of R 2 through R 6 ,R 12 , and R 13 is H and R a R b N—(CH 2 ) m is 1-piperazinylethyl and the 1-piperazinyl ring is optionally substituted at the 4-position with an optionally substituted phenyl or benzyl.
4. The compound of claim 1 , wherein m is 2; each of R 2 through R 6 ,R 12 , and R 13 is H; and R a R b N—(CH 2 ) m is
5. The compound of claim 1 , wherein m is 2; each of R 2 , R 3 , R 4 , R 5 , R 6 , R 12 , and R 13 is hydrogen; and R a R b N is cyclic amino or an imido ring.
6. The compound of claim 5 , wherein R a R b N is cyclic amino.
7. The compound of claim 5 , wherein R a R b N is an imido ring.
8. The compound of claim 1 , wherein
R 2 is hydrogen;
R 3 is CH 2 NR 7 R 8 (where each of R 7 and R 8 is independently H—, alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or dialkylamino lower alkyl, or R 7 and R 8 taken together with —N— represent a cyclic amino-), NR 10 R 11 (where each of R 10 and R 11 is independently hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or di-lower alkyl, or R 10 and R 11 taken together with —N— represent a cyclic amino), or dialkylamino alkyl;
R 4 is lower alkoxy, hydroxy, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, or R 4 together with R 5 is methylenedioxy or ethylenedioxy;
R 5 is hydrogen, or together with R 4 is methylenedioxy or ethylenedioxy;
R 6 is hydrogen.
9. The compound of claim 8 , wherein R 3 is CH 2 NR 7 R 8 (where each of R 7 and R 8 is lower alkyl), R 4 is hydroxy, alkoxy or alkylcarbonyloxy and R 12 and R 13 are hydrogen.
10. The compound of claim 9 , wherein R 3 is CH 2 N(CH 3 ) 2 and R 4 is hydroxy.
11. The compound of claim 10 wherein m is 2 and R a and R b together with N form a 5- or 6-membered cyclic amino or cyclic imide ring.
12. The compound of claim 11 wherein R a R b together with N form a saturated 6-membered cyclic amine optionally having one additional nitrogen in the ring.
13. The compound of claim 12 , wherein the 6-membered cyclic amine is piperazine optionally substituted at the 4-position with phenyl, substituted phenyl, benzyl, or substituted benzyl.
14. The compound of claim 1 , wherein
R 2 is hydrogen, lower alkyl, or halogenated lower alkyl;
R 3 is hydrogen or lower alkyl;
R 4 is lower alkoxy, hydroxy, halogenated lower alkoxy, carbamoyloxy, lower alkylcarbonyloxy, or R 4 together with R 5 is methylenedioxy;
R 5 is hydrogen, or together with R 4 is methylenedioxy; and
R 6 is hydrogen.
15. The compound of claim 14 , wherein R 3 is hydrogen, R 5 is hydrogen, R 4 is carbamoyloxy and R 12 and R 13 are hydrogen.
16. The compound of claim 15 , wherein R 2 is lower alkyl and R 4 is 4-(1-piperidino)-1-piperidinocarbonyloxy.
17. The compound of claim 16 , wherein m is 2, R 2 is ethyl and R a and R b together with N form a cyclic imide ring.
18. The compound of claim 16 , wherein m is 2 and R a R b together with N form a saturated 5-, 6-, or 7-membered cyclic amine ring having no more than one additional nitrogen, oxygen, or sulfur atom in the ring, wherein the ring is unsubstituted or substituted with one or two substituents chosen from lower alkyl, lower cycloalkyl, phenyl, substituted phenyl (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, carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperidino, lower alkoxycarbonyl, and lower alkylcarbonylamino), benzyl, substituted benzyl (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, carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperidino, lower alkoxycarbonyl, and lower alkylcarbonylamino), aminocarbonylmethyl, lower alkylaminocarbonylmethyl, amino, mono- or di-lower alkylamino, cyclic amino, or a 5- or 6-membered heterocyclic ring 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.
19. The compound of claim 18 , wherein R a R b together with N form a saturated 6-membered cyclic amine optionally having one additional nitrogen in the ring.
20. The compound of claim 19 , wherein the 6-membered cyclic amine is piperazine optionally substituted at the 4-position with phenyl, substituted phenyl, benzyl, or substituted benzyl.
21. The compound of claim 1 , wherein
R 2 is lower alkyl;
R 3 is hydrogen;
R 4 is hydroxy, lower alkoxy, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy;
R 5 is hydrogen; and
R 6 is hydrogen.
22. The compound of claim 21 , wherein R 2 is ethyl, R 4 is hydroxy and R 12 and R 13 are hydrogen.
23. The compound of claim 22 , wherein m is 2 and R a and R b together with N form a 5- or 6-member cyclic imide ring.
24. The compound of claim 22 , wherein m is 2 and R a R b together with N form a saturated 5-, 6-, or 7-membered cyclic amine ring having no more than one additional nitrogen, oxygen, or sulfur atom in the ring, wherein the ring is unsubstituted or substituted with one or two substituents chosen from lower alkyl, lower cycloalkyl, phenyl, substituted phenyl (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, carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperidino, lower alkoxycarbonyl, and lower alkylcarbonylamino), benzyl, substituted benzyl (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, carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperidino, lower alkoxycarbonyl, and lower alkylcarbonylamino), aminocarbonylmethyl, lower alkylaminocarbonylmethyl, amino, mono- or di-lower alkylamino, cyclic amino, or a 5- or 6-membered heterocyclic ring 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.
25. The compound of claim 21 , wherein R a R b together with N form a saturated 6-membered cyclic amine optionally having one additional nitrogen in the ring.
26. The compound of claim 1 , wherein
each of R 2 , R 4 , R 5 , and R 6 is hydrogen;
R 3 is amino or nitro; and
R 12 and R 13 are independently hydrogen, lower alkyl, cyano, hydroxycarbonyl, lower alkoxycarbonyl, cycloalkyl, alkylcarbonylamino, 1-napthyl, 2-napthyl or phenyl.
27. The compound of claim 26 , wherein R 3 is amino and R 12 and R 13 are hydrogen.
28. The compound of claim 27 , wherein m is 2 and R a and R b together with N form a cyclic imide ring.
29. The compound of claim 27 , wherein m is 2 and R a R b together with N form a saturated 5-, 6-, or 7-membered cyclic amine ring having no more than one additional nitrogen, oxygen, or sulfur atom in the ring, wherein the ring is unsubstituted or substituted with one or two substituents chosen from lower alkyl, lower cycloalkyl, phenyl, substituted phenyl (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, carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperidino, lower alkoxycarbonyl, and lower alkylcarbonylamino), benzyl, substituted benzyl (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, carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperidino, lower alkoxycarbonyl, and lower alkylcarbonylamino), aminocarbonylmethyl, lower alkylaminocarbonylmethyl, amino, mono- or di-lower alkylamino, cyclic amino, or a 5- or 6-membered heterocyclic ring 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.
30. The compound of claim 29 , wherein R a R b together with N form a saturated 6-membered cyclic amine optionally having one additional nitrogen in the ring.
31. The compound of claim 29 , wherein R 3 is nitro.
32. The compound of claim 31 , wherein m is 2 and R a and R b together with N form a cyclic imide ring.
33. The compound of claim 31 , wherein m is 2 and R a R b together with N form a saturated 5-, 6-, or 7-membered cyclic amine ring having no more than one additional nitrogen, oxygen, or sulfur atom in the ring, wherein the ring is unsubstituted or substituted with one or two substituents chosen from lower alkyl, lower cycloalkyl, phenyl, substituted phenyl (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, carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperidino, lower alkoxycarbonyl, and lower alkylcarbonylamino), benzyl, substituted benzyl (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, carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperidino, lower alkoxycarbonyl, and lower alkylcarbonylamino), aminocarbonylmethyl, lower alkylaminocarbonylmethyl, amino, mono- or di-lower alkylamino, cyclic amino, or a 5- or 6-membered heterocyclic ring 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.
34. The compound of claim 33 , wherein R a R b together with N form a saturated 6-membered cyclic amine optionally having one additional nitrogen in the ring.
35. The compound of claim 1 , wherein
R 2 is tri-lower alkylsilyl;
R 3 is hydrogen;
R 4 is hydroxy, lower alkoxy, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy;
R 5 is hydrogen; and
R 6 is hydrogen.
36. The compound of claim 35 , wherein R 2 is t-butyldimethylsilyl, R 4 is hydroxy R 12 and R 13 are hydrogen.
37. The compound of claim 36 , wherein m is 2 and R a and R b together with N form a cyclic imide ring.
38. The compound of claim 36 , wherein m is 2 and R a R b together with N form a saturated 5-, 6-, or 7-membered cyclic amine ring having no more than one additional nitrogen, oxygen, or sulfur atom in the ring, wherein the ring is unsubstituted or substituted with one or two substituents chosen from lower alkyl, lower cycloalkyl, phenyl, substituted phenyl (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, carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperidino, lower alkoxycarbonyl, and lower alkylcarbonylamino), benzyl, substituted benzyl (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, carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperidino, lower alkoxycarbonyl, and lower alkylcarbonylamino), aminocarbonylmethyl, lower alkylaminocarbonylmethyl, amino, mono- or di-lower alkylamino, cyclic amino, or a 5- or 6-membered heterocyclic ring 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.
39. The compound of claim 38 , wherein R a R b together with N form a saturated 6-membered cyclic amine optionally having one additional nitrogen in the ring.
40. 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.
41. The pharmaceutical composition of claim 40 suitable for oral administration.
42. The pharmaceutical composition of claim 40 suitable for IV administration.
43. The pharmaceutical composition of claim 40 suitable for IM administration.
44. 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 .
45. The method of claim 44 , wherein the compound is administered orally.
46. The method of claim 44 , wherein the compound is administered IV.
47. The method of claim 44 , wherein the compound is administered parenterally.
48. A compound of the formula
wherein R is R a R b N—(CH 2 ) m ; m is an integer from 1-10; and
R 2 is —CH 2 NR 7 R 8 (where R 7 and R 8 taken together with —N— represent a cyclic amino) when R 3 and R 6 are H and R 4 and R 5 taken together represent ethylenedioxy; or
R 2 is butoxyiminomethyl when each of R 3 , R 4 , R 5 and R 6 is H; or
R 3 is trialkylsilylethylene when each of R 2 , R 4 , R 5 , and R 6 is H; or
R 2 and R 3 together represent —CH(NR 12 R 13 )—CH 2 —CH 2 — when R 4 is lower alkyl, R 5 is halo, and R 6 is H, wherein R 12 and R 13 each is independently H or lower alyl.
49. A pharmaceutical composition useful for treating cancer in a warm-blooded animal, which composition comprises compound as defined in claim 48 in combination with a pharmaceutically acceptable excipient.
50. 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 48 .