U.S. patent application number 10/500424 was filed with the patent office on 2005-10-13 for luminacin analogs and uses thereof.
Invention is credited to Fang, Francis, Johannes, Charles, Yao, Ye, Zhu, Xiaojie Jeff.
Application Number | 20050228039 10/500424 |
Document ID | / |
Family ID | 23347131 |
Filed Date | 2005-10-13 |
United States Patent
Application |
20050228039 |
Kind Code |
A1 |
Fang, Francis ; et
al. |
October 13, 2005 |
Luminacin analogs and uses thereof
Abstract
The present invention provides compounds having formula (I) (and
pharmaceutically acceptable derivatives thereof): 1 and
additionally provides methods for the synthesis thereof and methods
for the use thereof in the treatment of cancer, wherein
R.sub.1-R.sub.14 and n are as defined herein.
Inventors: |
Fang, Francis; (Andover,
MA) ; Johannes, Charles; (Newbury, MA) ; Yao,
Ye; (North Andover, MA) ; Zhu, Xiaojie Jeff;
(Andover, MA) |
Correspondence
Address: |
Choate Hall & Stewart
Patent Group
Exchange Place
53 State Street
Boston
MA
02109
US
|
Family ID: |
23347131 |
Appl. No.: |
10/500424 |
Filed: |
May 4, 2005 |
PCT Filed: |
December 18, 2002 |
PCT NO: |
PCT/US02/40744 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60343678 |
Dec 28, 2001 |
|
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|
Current U.S.
Class: |
514/456 ;
514/459; 549/332 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 9/00 20180101; C07D 309/10 20130101; C07D 493/10 20130101 |
Class at
Publication: |
514/456 ;
514/459; 549/332 |
International
Class: |
A61K 031/353; C07D
305/14; C07D 493/04 |
Claims
1. A compound having the structure: 103or pharmaceutically
acceptable derivative thereof; wherein n is 0, 1 or 2; R.sub.1 is
hydrogen or an aliphatic, heteroaliphatic, aryl or heteroaryl
moiety; R.sub.2 and R.sub.3 are each independently hydrogen, or,
when taken together, may be --O-- or --(CH.sub.2).sub.q--, wherein
q is 1, 2 or 3; R.sub.4 is hydrogen, hydroxyl, protected hydroxyl
or OR.sup.i, or an aliphatic or heteroaliphatic moiety, wherein
R.sup.i is an aliphatic or heteroaliphatic moiety; R.sub.5 is
hydrogen, hydroxyl, protected hydroxyl or OR.sup.ii, or an
aliphatic or heteroaliphatic moiety, wherein R.sup.ii is an
aliphatic or heteroaliphatic moiety, or wherein R.sub.1 and
R.sub.5, when taken together, may form a cycloaliphatic or
heterocycloaliphatic moiety comprising 6 to 12 atoms; R.sub.6 is
hydrogen, or an aliphatic, heteroaliphatic, aryl or heteroaryl
moiety; R.sub.7 is hydrogen, hydroxyl, protected hydroxyl,
OR.sup.iii, or an aliphatic or heteroaliphatic moiety, wherein
R.sup.iii is an aliphatic or heteroaliphatic moiety; R.sub.8 is
hydrogen, hydroxyl, protected hydroxyl or OR.sup.iv, wherein
R.sup.iv is an aliphatic or heteroaliphatic moiety; R.sub.9 is
hydrogen, --CF.sub.3, --CHO, imine, hydrazone, oxime, carboxylic
acid, carboxylic ester, acyl halide, ketone, amide, acetal,
anhydride, dihalide, epoxide, nitrile or an aliphatic or
heteroaliphatic moiety; R.sub.10 is hydroxyl or protected hydroxyl;
R.sub.11 and R.sub.12 are each independently hydrogen, hydroxyl or
OR.sup.v, or an aliphatic or heteroaliphatic moiety, or, when taken
together, may be --(C.dbd.O)--; wherein R.sup.v is an aliphatic or
heteroaliphatic moiety; and R.sub.13 and R.sub.14 are each
independently hydrogen, or an aliphatic, heteroaliphatic, aryl or
heteroaryl moiety; whereby each of the foregoing aliphatic and
heteroaliphatic moieties may independently be substituted or
unsubstituted, cyclic or acyclic, linear or branched, and whereby
each of the foregoing aryl and heteroaryl moieties may be
substituted or unsubstituted; with the proviso that: (a) when
R.sub.4, R.sub.5, R.sub.8 and R.sub.10 are each hydroxyl, R.sub.7
is hydrogen, R.sub.13 and R.sub.14 are each methyl, R.sub.2 and
R.sub.3, taken together, form an epoxide, and n is 1, the following
groups do not occur simultaneously as defined: (i) R.sub.1 is
methyl, R.sub.9 is hydrogen, (R.sub.11, R.sub.12) is (.dbd.O) and
R.sub.6 is ethyl or isopropyl; (ii) R.sub.1 is methyl, R.sub.9 is
CHO, (R.sub.11, R.sub.12) is (OMe, H) and R.sub.6 is ethyl, propyl
or isopropyl; (iii) R.sub.1 is methyl, R.sub.9 is CHO, R.sub.11 and
R.sub.12 are hydrogen and R.sub.6 is ethyl, propyl or isopropyl;
(iv) R.sub.1 is methyl, R.sub.9 is COCH.sub.3, R.sub.11 and
R.sub.12 are hydrogen and R.sub.6 is ethyl; and (v) R.sub.1 is
ethyl, R.sub.9 is CHO, R.sub.11, and R.sub.12 are hydrogen and
R.sub.6 is ethyl; and (b) when R.sub.1 is methyl, R.sub.2 and
R.sub.3, taken together, form an epoxide, R.sub.6 is ethyl, R.sub.7
is hydrogen, (R.sub.11, R.sub.12) is (OMe, H), R.sub.13 and
R.sub.14 are each methyl and n is 1, the following groups do not
occur simultaneously as defined: R.sub.4 and R.sub.5 is OH or OBn,
R.sub.8 and R.sub.10 is OH or --OCH.sub.2OCH.sub.3 and R.sub.9 is
--CHO, --CH.sub.2OH or --CH.sub.2OTBS.
2. The compound of claim 1 wherein n is 1 and the compound has the
structure: 104
3. The compound of claim 1 wherein R.sub.10 is hydroxyl and the
compound has the structure: 105
4. The compound of claim 1 wherein R.sub.14 is aryl and the
compound has the structure: 106
5. The compound of claim 1 wherein R.sub.2 and R.sub.3, taken
together, form an epoxide and the compound has the structure:
107
6. The compound of claim 1 wherein R.sub.4 is hydroxyl and the
compound has the structure: 108
7. The compound of claim 1 wherein R.sub.2 and R.sub.3, taken
together, form an epoxide, R.sub.4 and R.sub.10 are each hydroxyl,
R.sub.14 is aryl, n is 1 and the compound has the structure:
109
8. The compound of any one of claims 1, 2, 3, 4, 5, 6 or 7 wherein
R.sub.1 is hydrogen or lower alkyl, and wherein the alkyl
substitutent may be substituted or unsubstituted, linear or
branched or cyclic or acyclic.
9. The compound of any one of claim s 1, 2, 3, 4 or 6 wherein
R.sub.2 and R.sub.3, taken together, form a cyclopropyl moiety.
10. The compound of any one of claims 1, 2, 3, 4 or 6 wherein
R.sub.2 and R.sub.3, taken together, form an epoxide.
11. The compound of any one of claims 1, 2, 3, 4 or 5 wherein
R.sub.4 is hydroxyl.
12. The compound of any one of claims 1, 2, 3, 4, 5, 6 or 7 wherein
R.sub.5 is hydroxyl or lower alkoxyl, and wherein the alkoxyl
substitutent may be substituted or unsubstituted, linear or
branched or cyclic or acyclic.
13. The compound of any one of claims 1, 2, 3, 4, 5, 6 or 7 wherein
R.sub.6 is lower alkyl, and wherein the alkyl substitutent may be
substituted or unsubstituted, linear or branched or cyclic or
acyclic.
14. The compound of any one of claims 1, 2, 3, 4, 5, 6 or 7 wherein
R.sub.7 is hydrogen, hydroxyl, lower alkyl or lower alkoxyl, and
wherein the alkyl and alkoxyl substitutents may be substituted or
unsubstituted, linear or branched or cyclic or acyclic.
15. The compound of any one of claims 1, 2, 3, 4, 5, 6 or 7 wherein
R.sub.8 is hydrogen, hydroxyl or protected hydroxyl.
16. The compound of any one of claims 1, 2, 3, 4, 5, 6 or 7 wherein
R.sub.9 is --CHO or --CH.sub.2OR.sup.vi, wherein R.sup.vi is
hydrogen, protecting group or an aliphatic moiety, and wherein the
aliphatic moiety may be substituted or unsubstituted, linear or
branched or cyclic or acyclic.
17. The compound of any one of claims 1, 2, 4, 5 or 6 wherein
R.sub.10 is hydroxyl.
18. The compound of any one of claims 1, 2, 3, 4, 5, 6 or 7 wherein
R.sub.11 and R.sub.12 are independently hydrogen or lower alkoxyl,
and wherein the alkoxyl substitutent may be substituted or
unsubstituted, branched or unbranched or cyclic or acyclic.
19. The compound of any one of claims 1, 2, 3, 5 or 6 wherein
R.sub.13 and R.sub.14 are independently hydrogen, lower alkyl or
aryl, wherein the alkyl substitutent may be substituted or
unsubstituted, branched or unbranched or cyclic or acyclic, and
wherein the aryl substitutent may be substituted or
unsubstituted.
20. The compound of claim 4 or 7 wherein R.sub.13 is lower alkyl,
and wherein the alkyl substitutent may be substituted or
unsubstituted, linear or branched or cyclic or acyclic.
21. The compound of claim 7 wherein R.sub.1 is hydrogen or lower
alkyl, R.sub.5 is hydroxyl or lower alkoxyl, R.sub.6 is lower
alkyl, R.sub.7 is hydrogen, hydroxyl, lower alkyl or lower alkoxyl,
R.sub.8 is hydrogen, hydroxyl or protected hydroxyl, R.sub.9 is
--CHO or --CH.sub.2OR.sup.vi, R.sub.11 and R.sub.12 are
independently hydrogen or lower alkoxyl, and R.sub.13 is lower
alkyl; wherein R.sup.vi is hydrogen, protecting group or an
aliphatic or heteroaliphatic moiety; whereby each of the foregoing
alkyl, alkoxyl, aliphatic and heteroaliphatic moieties may be
independently substituted or unsubstituted, linear or branched, or
cyclic or acyclic.
22. A pharmaceutical composition comprising: a compound having the
structure: 110or pharmaceutically acceptable derivative thereof;
and a pharmaceutically acceptable carrier; wherein n is 0, 1 or 2;
R.sub.1 is hydrogen or an aliphatic, heteroaliphatic, aryl or
heteroaryl moiety; R.sub.2 and R.sub.3 are each independently
hydrogen, or, when taken together, may be --O-- or
--(CH.sub.2).sub.q--, where q is 1, 2 or 3; R.sub.4 is hydrogen,
hydroxyl, protected hydroxyl or OR.sup.i, or an aliphatic or
heteroaliphatic moiety, wherein R.sup.i is an aliphatic or
heteroaliphatic moiety; R.sub.5 is hydrogen, hydroxyl, protected
hydroxyl or OR.sup.ii, or an aliphatic or heteroaliphatic moiety,
wherein R.sup.ii is an aliphatic or heteroaliphatic moiety, or
wherein R.sub.1 and R.sub.5, when taken together, may form a
cycloaliphatic or heterocycloaliphatic moiety comprising 6 to 12
atoms; R is hydrogen, or an aliphatic, heteroaliphatic, aryl or
heteroaryl moiety; R.sub.7 is hydrogen, hydroxyl, protected
hydroxyl, OR.sup.iii, or an aliphatic or heteroaliphatic moiety,
wherein R.sup.iii is an aliphatic or heteroaliphatic moiety;
R.sub.8 is hydrogen, hydroxyl, protected hydroxyl or O.sup.iv,
wherein R.sup.iv is an aliphatic or heteroaliphatic moiety; R.sub.9
is hydrogen, --CF.sub.3, --CHO, imine, hydrazone, oxime, carboxylic
acid, carboxylic ester, acyl halide, ketone, amide, acetal,
anhydride, dihalide, epoxide, nitrile or an aliphatic or
heteroaliphatic moiety; R.sub.10 is hydroxyl or protected hydroxyl;
R.sub.11 and R.sub.12 are each independently hydrogen, hydroxyl or
OR.sup.v, or an aliphatic or heteroaliphatic moiety, or, when taken
together, may be --(C.dbd.O)--; wherein R.sup.v is an aliphatic or
heteroaliphatic moiety; and R.sub.13 and R.sub.14 are each
independently hydrogen, or an aliphatic, heteroaliphatic, aryl or
heteroaryl moiety; and pharmaceutically acceptable derivatives
thereof; whereby each of the foregoing aliphatic and
heteroaliphatic moieties may independently be substituted or
unsubstituted, cyclic or acyclic, linear or branched, and whereby
each of the foregoing aryl and heteroaryl moieties may be
substituted or unsubstituted; with the proviso that when R.sub.4,
R.sub.5, R.sub.8 and R.sub.10 are each hydroxyl, R.sub.7 is
hydrogen, R.sub.13 and R.sub.14 are each methyl, R.sub.2 and
R.sub.3, taken together, form an epoxide, and n is 1, the following
groups do not occur simultaneously as defined: (i) R.sub.1 is
methyl, R.sub.9 is hydrogen, (R.sub.11, R.sub.12) is (.dbd.O) and
R.sub.6 is ethyl or isopropyl; (ii) R.sub.1 is methyl, R.sub.9 is
CHO, (R.sub.11, R.sub.12) is (OMe, H) and R.sub.6 is ethyl, propyl
or isopropyl; (iii) R.sub.1 is methyl, R.sub.9 is CHO, R.sub.11 and
R.sub.12 are hydrogen and R.sub.6 is ethyl, propyl or isopropyl;
(iv) R.sub.1 is methyl, R.sub.9 is COCH.sub.3, R.sub.11 and
R.sub.12 are hydrogen and R.sub.6 is ethyl; and (v) R.sub.1 is
ethyl, R.sub.9 is CHO, R.sub.11 and R.sub.12 are hydrogen and
R.sub.6 is ethyl.
23. The pharmaceutical composition of claim 22 wherein n is 1 and
the compound has the structure: 111
24. The pharmaceutical composition of claim 22 wherein R.sub.10 is
hydroxyl and the compound has the structure: 112
25. The pharmaceutical composition of claim 22 wherein R.sub.14 is
aryl and the compound has the structure: 113
26. The pharmaceutical composition of claim 22 wherein R.sub.2 and
R.sub.3, taken together, form an epoxide, and the compound has the
structure: 114
27. The pharmaceutical composition of claim 22 wherein R.sub.4 is
hydroxyl and the compound has the structure: 115
28. The pharmaceutical composition of claim 22 wherein R.sub.2 and
R.sub.3, taken together, form an epoxide, R.sub.4 and R.sub.10 are
each hydroxyl, R.sub.14 is aryl, n is 1 and the compound has the
structure: 116
29. The pharmaceutical composition of any one of claims 22, 23, 24,
25, 26, 27 or 28 wherein R.sub.1 is hydrogen or lower alkyl, and
wherein the alkyl substitutent may be substituted or unsubstituted,
linear or branched or cyclic or acyclic.
30. The pharmaceutical composition of any one of claims 22, 23, 24,
25 or 27 wherein R.sub.2 and R.sub.3, taken together, form a
cyclopropyl moiety.
31. The pharmaceutical composition of any one of claims 22, 23, 24,
25 or 27 wherein R.sub.2 and R.sub.3, taken together, form an
epoxide.
32. The pharmaceutical composition of any one of claims 22, 23, 24,
25 or 26 wherein R.sub.4 is hydroxyl.
33. The pharmaceutical composition of any one of claims 22, 23, 24,
25, 26, 27 or 28 wherein R.sub.5 is hydroxyl or lower alkoxyl, and
wherein the alkoxyl substitutent may be substituted or
unsubstituted, linear or branched or cyclic or acyclic.
34. The pharmaceutical composition of any one of claims 22, 23, 24,
25, 26, 27 or 28 wherein R.sub.6 is lower alkyl, and wherein the
alkyl substitutent may be substituted or unsubstituted, linear or
branched or cyclic or acyclic.
35. The pharmaceutical composition of any one of claims 22, 23, 24,
25, 26, 27 or 28 wherein R.sub.7 is hydrogen, hydroxyl, lower alkyl
or lower alkoxyl, and wherein the alkyl and alkoxyl substitutents
may be substituted or unsubstituted, linear or branched or cyclic
or acyclic.
36. The pharmaceutical composition of any one of claims 22, 23, 24,
25, 26, 27 or 28 wherein R.sub.8 is hydrogen, hydroxyl or protected
hydroxyl.
37. The pharmaceutical composition of any one of claims 22, 23, 24,
25, 26, 27 or 28 wherein R.sub.9 is --CHO or --CH.sub.2OR.sup.vi,
wherein R.sup.vi is hydrogen, protecting group or an aliphatic
moiety, and wherein the aliphatic moiety may be substituted or
unsubstituted, linear or branched or cyclic or acyclic.
38. The pharmaceutical composition of any one of claims 22, 23, 25,
26 or 27 wherein R.sub.10 is hydroxyl.
39. The pharmaceutical composition of any one of claims 22, 23, 24,
25, 26, 27 or 28 wherein R.sub.11 and R.sub.12 are independently
hydrogen or lower alkoxyl, and wherein the alkoxyl substitutent may
be substituted or unsubstituted, branched or unbranched or cyclic
or acyclic.
40. The pharmaceutical composition of any one of claims 22, 23, 24,
26 or 27 wherein R.sub.13 and R.sub.14 are independently hydrogen,
lower alkyl or aryl, wherein the alkyl substitutent may be
substituted or unsubstituted, branched or unbranched or cyclic or
acyclic, and wherein the aryl substitutent may be substituted or
unsubstituted.
41. The pharmaceutical composition of claim 25 or 28 wherein
R.sub.13 is lower alkyl, and wherein the alkyl substitutent may be
substituted or unsubstituted, linear or branched or cyclic or
acyclic.
42. The pharmaceutical composition of claim 28 wherein R.sub.1 is
hydrogen or lower alkyl, R.sub.5 is hydroxyl or lower alkoxyl,
R.sub.6 is lower alkyl, R.sub.7 is hydrogen, hydroxyl, lower alkyl
or lower alkoxyl, R.sub.8 is hydrogen, hydroxyl or protected
hydroxyl, R.sub.9 is --CHO or --CH.sub.2OR.sup.vi, R.sub.11 and
R.sub.12 are independently hydrogen or lower alkoxyl, and R.sub.13
is lower alkyl; wherein R.sup.vi is hydrogen, protecting group or
an aliphatic or heteroaliphatic moiety; whereby each of the
foregoing alkyl, alkoxyl, aliphatic and heteroaliphatic moieties
may be independently substituted or unsubstituted, linear or
branched, or cyclic or acyclic.
43. A method for treating cancer comprising: administering to a
subject in need thereof a therapeutically effective amount of a
compound having the structure: 117or pharmaceutically acceptable
derivative thereof; wherein n is 0, 1 or 2; R.sub.1 is hydrogen or
an aliphatic, heteroaliphatic, aryl or heteroaryl moiety; R.sub.2
and R.sub.3 are each independently hydrogen, or, when taken
together, may be --O-- or --(CH.sub.2).sub.q--, where q is 1, 2 or
3; R.sub.4 is hydrogen, hydroxyl, protected hydroxyl or OR.sup.i,
or an aliphatic or heteroaliphatic moiety, wherein R.sup.i is an
aliphatic or heteroaliphatic moiety; R.sub.5 is hydrogen, hydroxyl,
protected hydroxyl or OR.sup.ii, or an aliphatic or heteroaliphatic
moiety, wherein R.sup.ii is an aliphatic or heteroaliphatic moiety,
or wherein R.sub.1 and R.sub.5, when taken together, may form a
cycloaliphatic or heterocycloaliphatic moiety comprising 6 to 12
atoms; R.sub.6 is hydrogen, or an aliphatic, heteroaliphatic, aryl
or heteroaryl moiety; R.sub.7 is hydrogen, hydroxyl, protected
hydroxyl, OR.sup.iii, or an aliphatic or heteroaliphatic moiety,
wherein R.sup.iii is an aliphatic or heteroaliphatic moiety;
R.sub.8 is hydrogen, hydroxyl, protected hydroxyl or OR.sup.iv,
wherein R.sup.iv is an aliphatic or heteroaliphatic moiety; R.sub.9
is hydrogen, --CF.sub.3, --CHO, imine, hydrazone, oxime, carboxylic
acid, carboxylic ester, acyl halide, ketone, amide, acetal,
anhydride, dihalide, epoxide, nitrile or an aliphatic or
heteroaliphatic moiety; R.sub.10 is hydroxyl or protected hydroxyl;
R.sub.11 and R.sub.12 are each independently hydrogen, hydroxyl or
OR.sup.v, or an aliphatic or heteroaliphatic moiety, or, when taken
together, may be --(C.dbd.O)--; wherein R.sup.v is an aliphatic or
heteroaliphatic moiety; and R.sub.13 and R.sub.14 are each
independently hydrogen, or an aliphatic, heteroaliphatic, aryl or
heteroaryl moiety; whereby each of the foregoing aliphatic and
heteroaliphatic moieties may independently be substituted or
unsubstituted, cyclic or acyclic, linear or branched, and whereby
each of the foregoing aryl and heteroaryl moieties may be
substituted or unsubstituted; with the proviso that when R.sub.4,
R.sub.5, R.sub.8 and R.sub.10 are each hydroxyl, R.sub.7 is
hydrogen, R.sub.13 and R.sub.14 are each methyl, R.sub.2 and
R.sub.3, taken together, form an epoxide, and n is 1, the following
groups do not occur simultaneously as defined: (i) R.sub.1 is
methyl, R.sub.9 is hydrogen, (R.sub.11, R.sub.12) is (.dbd.O) and
R.sub.6 is ethyl or isopropyl; (ii) R.sub.1 is methyl, R.sub.9 is
CHO, (R.sub.11, R.sub.12) is (OMe, H) and R.sub.6 is ethyl, propyl
or isopropyl; (iii) R.sub.1 is methyl, R.sub.9 is CHO, R.sub.11 and
R.sub.12 are hydrogen and R.sub.6 is ethyl, propyl or isopropyl;
(iv) R.sub.1 is methyl, R.sub.9 is COCH.sub.3, R.sub.11 and
R.sub.12 are hydrogen and R.sub.6 is ethyl; and (v) R.sub.1 is
ethyl, R.sub.9 is CHO, R.sub.11 and R.sub.12 are hydrogen and
R.sub.6 is ethyl.
45. The method of claim 43 wherein in the compound n is 1 and the
compound has the structure: 118
46. The method of claim 43 wherein in the compound R.sub.10 is
hydroxyl and the compound has the structure: 119
47. The method of claim 43 wherein in the compound R.sub.14 is aryl
and the compound has the structure: 120
48. The method of claim 43 wherein in the compound R.sub.2 and
R.sub.3, taken together, form an epoxide and the compound has the
structure: 121
49. The method of claim 43 wherein in the compound R.sub.4 is
hydroxyl and the compound has the structure: 122
50. The method of claim 43 wherein in the compound R.sub.2 and
R.sub.3, taken together, form an epoxide, R.sub.4 and R.sub.10 are
each hydroxyl, R.sub.14 is aryl, n is 1 and the compound has the
structure: 123
51. The method of any one of claims 43, 44, 45, 46, 47, 48, 49 or
50 wherein in the compound R.sub.1 is hydrogen or lower alkyl, and
wherein the alkyl substitutent may be substituted or unsubstituted,
linear or branched or cyclic or acyclic.
52. The method of any one of claims 43, 44, 45, 46, 47 or 49
wherein in the compound R.sub.2 and R.sub.3, taken together, form a
cyclopropyl moiety.
53. The method of any one of claims 43, 44, 45, 46, 47 or 49
wherein in the compound R.sub.2 and R.sub.3, taken together, form
an epoxide.
54. The method of any one of claims 43, 44, 45, 46, 47 or 48
wherein in the compound R.sub.4 is hydroxyl.
55. The method of any one of claims 43, 44, 45, 46, 47, 48, 49 or
50 wherein in the compound R.sub.5 is hydroxyl or lower alkoxyl,
and wherein the alkoxyl substitutent may be substituted or
unsubstituted, linear or branched or cyclic or acyclic.
56. The method of any one of claims 43, 44, 45, 46, 47, 48, 49 or
50 wherein in the compound R.sub.6 is lower alkyl, and wherein the
alkyl substitutent may be substituted or unsubstituted, linear or
branched or cyclic or acyclic.
57. The method of any one of claims 43, 44, 45, 46, 47, 48, 49 or
50 wherein in the compound R.sub.7 is hydrogen, hydroxyl, lower
alkyl or lower alkoxyl, and wherein the alkyl and alkoxyl
substitutents may be substituted or unsubstituted, linear or
branched or cyclic or acyclic.
58. The method of any one of claims 43, 44, 45, 46, 47, 48, 49 or
50 wherein in the compound R.sub.8 is hydrogen, hydroxyl or
protected hydroxyl.
59. The method of any one of claims 43, 44, 45, 46, 47, 48, 49 or
50 wherein in the compound R.sub.9 is --CHO or --CH.sub.2OR.sup.vi,
wherein R.sup.vi is hydrogen, protecting group or an aliphatic
moiety, and wherein the aliphatic moiety may be substituted or
unsubstituted, linear or branched or cyclic or acyclic.
60. The method of any one of claims 43, 44, 45, 47, 48 or 49
wherein in the compound R.sub.10 is hydroxyl.
61. The method of any one of claims 43, 44, 45, 46, 47, 48, 49 or
50 wherein in the compound R.sub.11 and R.sub.12 are independently
hydrogen or lower alkoxyl, and wherein the alkoxyl substitutent may
be substituted or unsubstituted, branched or unbranched or cyclic
or acyclic.
62. The method of any one of claims 43, 44, 45, 46, 48 or 49
wherein in the compound R.sub.13 and R.sub.14 are independently
hydrogen, lower alkyl or aryl, wherein the alkyl substitutent may
be substituted or unsubstituted, branched or unbranched or cyclic
or acyclic, and wherein the aryl substitutent may be substituted or
unsubstituted.
63. The method of claim 47 or 50 wherein in the compound R.sub.13
is lower alkyl, and wherein the alkyl substitutent may be
substituted or unsubstituted, linear or branched or cyclic or
acyclic.
64. The method of claim 50 wherein in the compound R.sub.1 is
hydrogen or lower allyl, R.sub.5 is hydroxyl or lower alkoxyl,
R.sub.6 is lower alkyl, R.sub.7 is hydrogen, hydroxyl, lower alkyl
or lower alkoxyl, R.sub.8 is hydrogen, hydroxyl or protected
hydroxyl, R.sub.9 is --CHO or --CH.sub.2OR.sup.vi, R.sub.11 and
R.sub.12 are independently hydrogen or lower alkoxyl, and R.sub.13
is lower alkyl; wherein R.sup.vi is hydrogen, protecting group or
an aliphatic or heteroaliphatic moiety; whereby each of the
foregoing alkyl, alkoxyl, aliphatic and heteroaliphatic moieties
may be independently substituted or unsubstituted, linear or
branched, or cyclic or acyclic.
Description
PRIORITY CLAIM
[0001] The present application claims priority to U.S. Patent
Application Ser. No. 60/343,678, filed Dec. 28, 2001, the entire
contents of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Luminacins are novel angiogenesis inhibitors isolated from
the fermentation broth of an actinomycete strain designated
Streptomyces sp. Mer-VD1207. (Naruse et al. The Journal of
Antibiotics, 2000, Vol. 53, No. 6, 579-590). Fourteen active
components were isolated, the structures of which are shown
below.
1 2 Luminacin Component R.sub.1 R.sub.2 R.sub.3 R.sub.4, R.sub.5
A.sub.1 H Et H .dbd.O A.sub.2 H Et H .dbd.O B.sub.1 H iPr H .dbd.O
B.sub.2 H iPr H .dbd.O C.sub.1 H Et CHO OMe, H C.sub.2 H Et CHO
OMe, H D.sub. H Et CHO H, H E.sub.1 H iPr CHO OMe, H E.sub.2 H iPr
CHO OMe, H E.sub.3 H Pr CHO OMe, H F.sub. CH.sub.3 Et CHO H, H
G.sub.1 H iPr CHO H, H G.sub.2 H Pr CHO H, H H.sub. H Et COCH.sub.3
H, H
[0003] The luminacin components were tested in a rat aorta tube
formation (RATF) model, and were shown to inhibit branching and
tube formation without decreasing the number of migrating cells
(Wakabayashi et al. The Journal of Antibiotics, 2000, Vol. 53, No.
6, 591-596). This activity was confirmed in another angiogenesis
model using human umbilical vein endothelial cells (HUVEC). The
inhibitory activities toward tube formation (RATF model and TF
model) and endothelial cell proliferation suggest that these
compounds are angiogenesis inhibitors. Molecules closely related or
identical to C.sub.1 and C.sub.2 have also been reported to exhibit
activities of immunosuppression (Suzuki et al., Kokai Tokkyo Koho,
1983, 116, 686) and low density lipoprotein (LDL) uptake
enhancement (Hamaguchi et al., Kokai Tokkyo Koho, 1994, 228, 144).
The relationship, if any, of these activites to the angiogenic
activity remains to be established.
[0004] The newly developing field of angiogenesis inhibitors has
vast applications in the treatment of many incurable diseases like
cancer. Thus these types of compounds have the potential to
significantly impact modern medicine. Accordingly, the demonstrated
ability of luminacins to inhibit angiogenesis has generated an
interest in further exploring the biological and pharmacological
activity of luminacins and analogues thereof. Clearly, there
remains a need to develop practical synthetic methodologies to
access and examine the therapeutic effect of a variety of novel
luminacin analogues, particularly those that are inaccessible by
making modifications to the natural product. It would also be of
particular interest to develop novel compounds that exhibit a
favorable therapeutic profile in vivo (e.g., are safe and
effective, while retaining stability in biological media).
SUMMARY OF THE INVENTION
[0005] As discussed above, there remains a need for the development
of novel therapeutic agents and agents useful for treating
disorders that involve angiogenic activity. The present invention
provides novel compounds of general formula (I), 3
[0006] and pharmaceutical compositions thereof, as described
generally and in subclasses herein, which compounds are useful as
angiogenesis inhibitors, and thus are useful, for example, for the
treatment of angiogenesis-related disorders, including, for
example, cancer or proliferative disorders.
DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE INVENTION
[0007] In recognition of the need to develop novel and effective
cancer therapies, the present invention provides novel synthetic
methodologies enabling access to luminacin analogs having a broad
range of biological and pharmacological activity. In one aspect,
the present invention provides novel luminacin compounds, as
described in more detail herein, which demonstrate potent
anti-angiogenesis activity. Thus, the compounds of the invention,
and pharmaceutical compositions thereof, are useful as angiogenesis
inhibitors for the treatment of cancer.
[0008] 1) General Description of Compounds of the Invention
[0009] The compounds of the invention include compounds of the
general formula (I) as further defined below: 4
[0010] and pharmaceutically acceptable derivatives thereof,
[0011] wherein n is 0, 1 or 2;
[0012] R.sub.1 is hydrogen or an aliphatic, heteroaliphatic, aryl
or heteroaryl moiety;
[0013] R.sub.2 and R.sub.3 are each independently hydrogen, or,
when taken together, may be --O-- or --(CH.sub.2).sub.q--, where q
is 1, 2 or 3;
[0014] R.sub.4 is hydrogen, hydroxyl, protected hydroxyl or
OR.sup.i, or an aliphatic or heteroaliphatic moiety,
[0015] wherein R.sup.i is an aliphatic or heteroaliphatic
moiety;
[0016] R.sub.5 is hydrogen, hydroxyl, protected hydroxyl or
OR.sup.ii, or an aliphatic or heteroaliphatic moiety,
[0017] wherein R.sup.ii is an aliphatic or heteroaliphatic moiety,
or wherein R.sub.1 and R.sub.5, when taken together, may form a
cycloaliphatic or heterocycloaliphatic moiety comprising 6 to 12
atoms;
[0018] R.sub.6 is hydrogen, or an aliphatic, heteroaliphatic, aryl
or heteroaryl moiety;
[0019] R.sub.7 is hydrogen, hydroxyl, protected hydroxyl,
OR.sup.iii, or an aliphatic or heteroaliphatic moiety,
[0020] wherein R.sup.iii is an aliphatic or heteroaliphatic
moiety;
[0021] R.sub.8 is hydrogen, hydroxyl, protected hydroxyl or
OR.sup.iv, wherein R.sup.iv is an aliphatic or heteroaliphatic
moiety;
[0022] R.sub.9 is hydrogen, --CF.sub.3, --CHO, imine, hydrazone,
oxime, carboxylic acid, carboxylic ester, acyl halide, ketone,
amide, acetal, anhydride, dihalide, epoxide, nitrile or an
aliphatic or heteroaliphatic moiety;
[0023] R.sub.10 is hydroxyl or protected hydroxyl;
[0024] R.sub.11 and R.sub.12 are each independently hydrogen,
hydroxyl or OR.sup.v, or an aliphatic or heteroaliphatic moiety,
or, when taken together, may be --C.dbd.O)--;
[0025] wherein R.sup.v is an aliphatic or heteroaliphatic
moiety;
[0026] and R.sub.13 and R.sub.14 are each independently hydrogen,
or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;
[0027] whereby each of the foregoing aliphatic and heteroaliphatic
moieties may independently be substituted or unsubstituted, cyclic
or acyclic, linear or branched, and whereby each of the foregoing
aryl and heteroaryl moieties may be substituted or
unsubstitued.
[0028] In certain embodiments of compounds described directly above
and compounds as described in certain classes and subclasses
herein, the following groups do not occur simultaneously as
defined:
[0029] R.sub.4, R.sub.5, R.sub.8 and R.sub.10 are hydroxyl,
R.sub.13 and R.sub.14 are methyl, R.sub.2 and R.sub.3 are taken
together to form an epoxide, n is 1 and:
[0030] (i) R.sub.1 is methyl, R.sub.9 is hydrogen, (R.sub.11,
R.sub.12) is (.dbd.O) and R.sub.6 is ethyl or isopropyl;
[0031] (ii) R.sub.1 is methyl drogen, R.sub.9 is CHO, (R.sub.11,
R.sub.12) is (OMe, H) and R.sub.6 is ethyl, propyl or
isopropyl;
[0032] (iii) R.sub.1 is methyl, R.sub.9 is CHO, R.sub.11 and
R.sub.12 are hydrogen and R.sub.6 is ethyl, propyl or
isopropyl;
[0033] (iv) R.sub.1 is methyl, R.sub.9 is COCH.sub.3, R.sub.11 and
R.sub.12 are hydrogen and R.sub.6 is ethyl; and
[0034] (v) R.sub.1 is ethyl, R.sub.9 is CHO, R.sub.11 and R.sub.12
are hydrogen and R.sub.6 is ethyl.
[0035] In certain embodiments, the present invention defines
certain classes of compounds which are of special interest. For
example, one class of compounds of special interest includes those
compounds in which n is 1 and the compound has the structure: 5
[0036] wherein R.sub.1-R.sub.14 are as previously defined.
[0037] Another class of compounds of special interest consists of
compounds in which R.sub.10 is OH and the compound has the
structure: 6
[0038] wherein R.sub.1-R.sub.9, R.sub.11-R.sub.14 and n are as
previously defined.
[0039] Another class of compounds of special interest consists of
compounds in which R.sub.14 is aryl and the compound has the
structure: 7
[0040] wherein R.sub.1-R.sub.13 and n are as previously
defined.
[0041] Another class of compounds of special interest consists of
compounds in which R.sub.2 and R.sub.3, taken together, form an
epoxide and the compound has the structure: 8
[0042] wherein R.sub.1, R.sub.4-R.sub.14 and n are as previously
defined.
[0043] Another class of compounds of special interest consists of
compounds in which R.sub.4 is hydroxyl and the compound has the
structure: 9
[0044] wherein R.sub.1-R.sub.3, R.sub.5-R.sub.14 and n are as
previously defined.
[0045] A number of important subclasses of each of the foregoing
classes deserve separate mention; these subclasses include
subclasses of the foregoing classes in which:
[0046] i) R.sub.1 is hydrogen or lower alkyl, wherein the alkyl
substitutent may be substituted or unsubstituted, linear or
branched or cyclic or acyclic;
[0047] ii) R.sub.2 and R.sub.3 are independently hydrogen or, when
taken together, form a cyclopropyl moiety or an epoxide;
[0048] iii) R.sub.4 is hydroxyl;
[0049] iv) R.sub.5 is hydroxyl or lower alkoxyl, wherein the
alkoxyl substitutent may be substituted or unsubstituted, linear or
branched or cyclic or acyclic;
[0050] v) R.sub.6 is lower alkyl, wherein the alkyl substitutent
may be substituted or unsubstituted, linear or branched or cyclic
or acyclic;
[0051] vi) R.sub.7 is hydrogen, hydroxyl, lower alkyl or lower
alkoxyl, wherein the alkyl and alkoxyl substitutents may be
substituted or unsubstituted, linear or branched or cyclic or
acyclic;
[0052] vii) R.sub.8 is hydrogen, hydroxyl or protected
hydroxyl;
[0053] viii) R.sub.9 is --CHO or --CH.sub.2OR.sup.vi, wherein
R.sup.vi is hydrogen, protecting group or an aliphatic moiety,
wherein the aliphatic moiety may be substituted or unsubstituted,
linear or branched or cyclic or acyclic;
[0054] ix) R.sub.10 is hydroxyl;
[0055] x) R.sub.11 and R.sub.12 are independently hydrogen or lower
alkoxyl, wherein the alkoxyl substitutent may be substituted or
unsubstituted, branched or unbranched or cyclic or acyclic;
[0056] xi) R.sub.13 and R.sub.14 are independently hydrogen, lower
alkyl or aryl, wherein the alkyl substitutent may be substituted or
unsubstituted, branched or unbranched or cyclic or acyclic, and
wherein the aryl substitutent may be substituted or unsubstituted;
and/or
[0057] xi) R.sub.5 is hydroxyl or lower alkoxyl, R.sub.6 is lower
alkyl, R.sub.7 is hydrogen, hydroxyl, lower alkyl or lower alkoxyl,
R.sub.8 is hydrogen, hydroxyl or protected hydroxyl, R.sub.9 is
--CHO or --CH.sub.2OR.sup.vi, R.sub.11 and R.sub.12 are
independently hydrogen or lower alkoxyl, and R.sub.13 is lower
alkyl; wherein R.sup.vi is hydrogen, protecting group or an
aliphatic or heteroaliphatic moiety; whereby each of the foregoing
alkyl, alkoxyl, aliphatic and heteroaliphatic moieties may be
independently substituted or unsubstituted, linear or branched, or
cyclic or acyclic.
[0058] The following structures illustrate several exemplary types
of compounds of these classes. Additional compounds are described
in the Exemplification herein. Other compounds of the invention
will be readily apparent to the reader: 10
[0059] As the reader will appreciate, compounds of particular
interest include, among others, those which share the attributes of
one or more of the foregoing subclasses. Some of those subclasses
are ilustrated by the following sorts of compounds:
[0060] I) Compounds of the Formula (and Pharmaceutically Acceptable
Derivatives Thereof): 11
[0061] wherein n is 0, 1 or 2;
[0062] R.sub.1 is hydrogen or lower alkyl;
[0063] R.sub.2 and R.sub.3 are independently hydrogen or, when
taken together, form a cyclopropyl moiety or an epoxide;
[0064] R.sub.4 is hydrogen, hydroxyl or protected hydroxyl;
[0065] R.sub.5 is hydroxyl or lower alkoxyl;
[0066] R.sub.6 is lower alkyl;
[0067] R.sub.7 is hydrogen, hydroxyl, lower alkyl or lower
alkoxyl;
[0068] R.sub.8 is hydrogen, hydroxyl or protected hydroxyl;
[0069] R.sub.9 is --CHO or --CH.sub.2OR.sup.vi, wherein R.sup.vi is
hydrogen, protecting group or an aliphatic moiety;
[0070] R.sub.10 is hydroxyl or protected hydroxyl;
[0071] R.sub.11 and R.sub.12 are independently hydrogen or lower
alkoxyl; and
[0072] R.sub.13 and R.sub.14 are independently hydrogen, lower
alkyl or aryl;
[0073] whereby each of the foregoing alkyl, alkoxyl and aliphatic
moieties may independently be substituted or unsubstituted, cyclic
or acyclic, linear or branched, and whereby each of the foregoing
aryl moieties may be substituted or unsubstitued.
[0074] II) Compounds of the Formula (and Pharmaceutically
Acceptable Derivatives Thereof): 12
[0075] wherein R.sub.1 is hydrogen or an aliphatic,
heteroaliphatic, aryl or heteroaryl moiety;
[0076] R.sub.5 is hydrogen, hydroxyl, protected hydroxyl or
OR.sup.ii, or an aliphatic or heteroaliphatic moiety,
[0077] wherein R.sup.ii is an aliphatic or heteroaliphatic moiety,
or wherein R.sub.1 and R.sub.5, when taken together, may form a
cycloaliphatic or heterocycloaliphatic moiety comprising 6 to 12
atoms;
[0078] R.sub.6 is hydrogen, or an aliphatic, heteroaliphatic, aryl
or heteroaryl moiety;
[0079] R.sub.7 is hydrogen, hydroxyl, protected hydroxyl,
OR.sup.iii, or an aliphatic or heteroaliphatic moiety,
[0080] wherein R.sup.iii is an aliphatic or heteroaliphatic
moiety;
[0081] R.sub.8 is hydrogen, hydroxyl, protected hydroxyl or
OR.sup.iv,
[0082] wherein R.sup.iv is an aliphatic or heteroaliphatic
moiety;
[0083] R.sub.9 is hydrogen, --CF.sub.3, --CHO, imine, hydrazone,
oxime, carboxylic acid, carboxylic ester, acyl halide, ketone,
amide, acetal, anhydride, dihalide, epoxide, nitrile or an
aliphatic or heteroaliphatic moiety;
[0084] R.sub.11 and R.sub.12 are each independently hydrogen,
hydroxyl or OR.sup.v, or an aliphatic or heteroaliphatic moiety,
or, when taken together, may be --(C.dbd.O)--;
[0085] wherein R.sup.v is an aliphatic or heteroaliphatic
moiety;
[0086] R.sub.13 is independently hydrogen, or an aliphatic,
heteroaliphatic, aryl or heteroaryl moiety; and
[0087] Ar is aryl;
[0088] whereby each of the foregoing aliphatic and heteroaliphatic
moieties may independently be substituted or unsubstituted, cyclic
or acyclic, linear or branched, and whereby each of the foregoing
aryl and heteroaryl moieties may be substituted or
unsubstitued.
[0089] III) Compounds of the Formula (and Pharmaceutically
Acceptable Derivatives Thereof): 13
[0090] wherein R.sub.1 is hydrogen or lower alkyl;
[0091] R.sub.5 is hydroxyl or lower alkoxyl;
[0092] R.sub.6 is lower alkyl;
[0093] R.sub.7 is hydrogen, hydroxyl, lower alkyl or lower
alkoxyl;
[0094] R.sub.8 is hydrogen, hydroxyl or protected hydroxyl;
[0095] R.sub.9 is --CHO or --CH.sub.2OR.sup.vi;
[0096] wherein R.sup.vi is hydrogen, protecting group or an
aliphatic or heteroaliphatic moiety;
[0097] R.sub.11 and R.sub.12 are independently hydrogen or lower
alkoxyl;
[0098] R.sub.13 is lower alkyl; and
[0099] Ar is aryl;
[0100] whereby each of the foregoing alkyl, alkoxyl, aliphatic and
heteroaliphatic moieties may be independently substituted or
unsubstituted, linear or branched, or cyclic or acyclic.
[0101] Some of the foregoing compounds can comprise one or more
asymmetric centers, and thus can exist in various isomeric forms,
e.g., stereoisomers and/or diastereomers. Thus, inventive compounds
and pharmaceutical compositions thereof may be in the form of an
individual enantiomer, diastereomer or geometric isomer, or may be
in the form of a mixture of stereoisomers. In certain embodiments,
the compounds of the invention are enantiopure compounds. In
certain other embodiments, mixtures of stereoisomers or
diastereomers are provided.
[0102] Furthermore, certain compounds, as described herein may have
one or more double bonds that can exist as either the Z or E
isomer, unless otherwise indicated. The invention additionally
encompasses the compounds as individual isomers substantially free
of other isomers and alternatively, as mixtures of various isomers,
e.g., racemic mixtures of stereoisomers. In addition to the
above-mentioned compounds per se, this invention also encompasses
pharmaceutically acceptable derivatives of these compounds and
compositions comprising one or more compounds of the invention and
one or more pharmaceutically acceptable excipients or
additives.
[0103] Compounds of the invention may be prepared by
crystallization of compound of formula (I) under different
conditions and may exist as one or a combination of polymorphs of
compound of general formula (I) forming part of this invention. For
example, different polymorphs may be identified and/or prepared
using different solvents, or different mixtures of solvents for
recrystallization; by performing crystallizations at different
temperatures; or by using various modes of cooling, ranging from
very fast to very slow cooling during crystallizations. Polymorphs
may also be obtained by heating or melting the compound followed by
gradual or fast cooling. The presence of polymorphs may be
determined by solid probe NMR spectroscopy, IR spectroscopy,
differential scanning calorimetry, powder X-ray diffractogram
and/or other techniques. Thus, the present invention encompasses
inventive compounds, their derivatives, their tautomeric forms,
their stereoisomers, their polymorphs, their pharmaceutically
acceptable salts their pharmaceutically acceptable solvates and
pharmaceutically acceptable compositions containing them.
[0104] 2) Compounds and Definitions
[0105] As discussed above, this invention provides novel compounds
with a range of biological properties. Compounds of this invention
have biological activities relevant for the treatment of diseases
or other disorders such as proliferative diseases, including, but
not limited to cancer. More generally, the compounds are useful in
the regulation of angiogenesis.
[0106] Compounds of this invention include those specifically set
forth above and described herein, and are illustrated in part by
the various classes, subgenera and species disclosed elsewhere
herein.
[0107] Additionally, the present invention provides
pharmaceutically acceptable derivatives of the inventive compounds,
and methods of treating a subject using these compounds,
pharmaceutical compositions thereof, or either of these in
combination with one or more additional therapeutic agents. The
phrase, "pharmaceutically acceptable derivative", as used herein,
denotes any pharmaceutically acceptable salt, ester, or salt of
such ester, of such compound, or any other adduct or derivative
which, upon administration to a patient, is capable of providing
(directly or indirectly) a compound as otherwise described herein,
or a metabolite or residue thereof. Pharmaceutically acceptable
derivatives thus include among others pro-drugs. A pro-drug is a
derivative of a compound, usually with significantly reduced
pharmacological activity, which contains an additional moiety which
is susceptible to removal in vivo yielding the parent molecule as
the pharmacologically active species. An example of a pro-drug is
an ester which is cleaved in vivo to yield a compound of interest.
Pro-drugs of a variety of compounds, and materials and methods for
derivatizing the parent compounds to create the pro-drugs, are
known and may be adapted to the present invention. Certain
exemplary pharmaceutical compositions and pharmaceutically
acceptable derivatives will be discussed in more detail herein
below.
[0108] Certain compounds of the present invention, and definitions
of specific functional groups are also described in more detail
below. For purposes of this invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed.,
inside cover, and specific functional groups are generally defined
as described therein. Additionally, general principles of organic
chemistry, as well as specific functional moieties and reactivity,
are described in "Organic Chemistry", Thomas Sorrell, University
Science Books, Sausalito: 1999; the entire contents of which are
incorporated herein by reference. Furthermore, it will be
appreciated by one of ordinary skill in the art that the synthetic
methods, as described herein, utilize a variety of protecting
groups. By the term "protecting group", has used herein, it is
meant that a particular functional moiety, e.g., O, S, or N, is
temporarily blocked so that a reaction can be carried out
selectively at another reactive site in a multifunctional compound.
In preferred embodiments, a protecting group reacts selectively in
good yield to give a protected substrate that is stable to the
projected reactions; the protecting group must be selectively
removed in good yield by readily available, preferably nontoxic
reagents that do not attack the other functional groups; the
protecting group forms an easily separable derivative (more
preferably without the generation of new stereogenic centers); and
the protecting group has a minimum of additional functionality to
avoid further sites of reaction. As detailed herein, oxygen,
sulfur, nitrogen and carbon protecting groups may be utilized. For
example, in certain embodiments, as detailed herein, certain
exemplary oxygen protecting groups are utilized. These oxygen
protecting groups include, but are not limited to methyl ethers,
substituted methyl ethers (e.g., MOM (methoxymethyl ether), MTM
(methylthiomethyl ether), BOM (benzyloxymethyl ether), PMBM
(p-methoxybenzyloxymethyl ether), to name a few), substituted ethyl
ethers, substituted benzyl ethers, silyl ethers (e.g., TMS
(trimethylsilyl ether), TES (triethylsilylether), TIPS
(triisopropylsilyl ether), TBDMS (t-butyldimethylsilyl ether),
tribenzyl silyl ether, TBDPS (t-butyldiphenyl silyl ether), to name
a few), esters (e.g., formate, acetate, benzoate (Bz),
trifluoroacetate, dichloroacetate, to name a few), carbonates,
cyclic acetals and ketals. In certain other exemplary embodiments,
nitrogen protecting groups are utilized. These nitrogen protecting
groups include, but are not limited to, carbamates (including
methyl, ethyl and substituted ethyl carbamates (e.g., Troc), to
name a few) amides, cyclic imide derivatives, N-Alkyl and N-Aryl
amines, imine derivatives, and enamine derivatives, to name a few.
Certain other exemplary protecting groups are detailed herein,
however, it will be appreciated that the present invention is not
intended to be limited to these protecting groups; rather, a
variety of additional equivalent protecting groups can be readily
identified using the above criteria and utilized in the present
invention. Additionally, a variety of protecting groups are
described in "Protective Groups in Organic Synthesis" Third Ed.
Greene, T. W. and Wuts, P. G., Eds., John Wiley & Sons, New
York: 1999, the entire contents of which are hereby incorporated by
reference.
[0109] It will be appreciated that the compounds, as described
herein, may be substituted with any number of substituents or
functional moieties. In general, the term "substituted" whether
preceded by the term "optionally" or not, and substituents
contained in formulas of this invention, refer to the replacement
of hydrogen radicals in a given structure with the radical of a
specified substituent. When more than one position in any given
structure may be substituted with more than one substituent
selected from a specified group, the substituent may be either the
same or different at every position. As used herein, the term
"substituted" is contemplated to include all permissible
substituents of organic compounds. In a broad aspect, the
permissible substituents include acyclic and cyclic, branched and
unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic
substituents of organic compounds. For purposes of this invention,
heteroatoms such as nitrogen may have hydrogen substituents and/or
any permissible substituents of organic compounds described herein
which satisfy the valencies of the heteroatoms. Furthermore, this
invention is not intended to be limited in any manner by the
permissible substituents of organic compounds. Combinations of
substituents and variables envisioned by this invention are
preferably those that result in the formation of stable compounds
useful in the treatment, for example of proliferative disorders,
including, but not limited to cancer. The term "stable", as used
herein, preferably refers to compounds which possess stability
sufficient to allow manufacture and which maintain the integrity of
the compound for a sufficient period of time to be detected and
preferably for a sufficient period of time to be useful for the
purposes detailed herein.
[0110] The term "aliphatic", as used herein, includes both
saturated and unsaturated, straight chain (i.e., unbranched),
branched, cyclic, or polycyclic aliphatic hydrocarbons, which are
optionally substituted with one or more functional groups. As will
be appreciated by one of ordinary skill in the art, "aliphatic" is
intended herein to include, but is not limited to, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus,
as used herein, the term "alkyl" includes straight, branched and
cyclic alkyl groups. An analogous convention applies to other
generic terms such as "alkenyl", "alkynyl" and the like.
Furthermore, as used herein, the terms "alkyl", "alkenyl",
"alkynyl" and the like encompass both substituted and unsubstituted
groups. In certain embodiments, as used herein, "lower alkyl" is
used to indicate those alkyl groups (cyclic, acyclic, substituted,
unsubstituted, branched or unbranched) having 1-6 carbon atoms.
[0111] In certain embodiments, the alkyl, alkenyl and alkynyl
groups employed in the invention contain 1-20 aliphatic carbon
atoms. In certain other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain 1-10 aliphatic
carbon atoms. In yet other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain 1-8 aliphatic
carbon atoms. In still other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain 1-6 aliphatic
carbon atoms. In yet other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain 1-4 carbon atoms.
Illustrative aliphatic groups thus include, but are not limited to,
for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,
--CH.sub.2-cyclopropyl, allyl, n-butyl, sec-butyl, isobutyl,
tert-butyl, cyclobutyl, --CH.sub.2-cyclobutyl, n-pentyl,
sec-pentyl, isopentyl, tert-pentyl, cyclopentyl,
--CH.sub.2-cyclopentyl-n, hexyl, sec-hexyl, cyclohexyl,
--CH.sub.2-cyclohexyl moieties and the like, which again, may bear
one or more substituents. Alkenyl groups include, but are not
limited to, for example, ethenyl, propenyl, butenyl,
1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups
include, but are not limited to, ethynyl, 2-propynyl (propargyl),
1-propynyl and the like.
[0112] The term "alkoxy" (or "alkyloxy"), or "thioalkyl" as used
herein refers to an alkyl group, as previously defined, attached to
the parent molecular moiety through an oxygen atom or through a
sulfur atom. In certain embodiments, the alkyl group contains 1-20
aliphatic carbon atoms. In certain other embodiments, the alkyl
group contains 1-10 aliphatic carbon atoms. In yet other
embodiments, the alkyl group employed in the invention contains 1-8
aliphatic carbon atoms. In still other embodiments, the alkyl group
contains 1-6 aliphatic carbon atoms. In yet other embodiments, the
alkyl group contains 1-4 aliphatic carbon atoms. Examples of
alkoxy, include but are not limited to, methoxy, ethoxy, propoxy,
isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
Examples of thioalkyl include, but are not limited to, methylthio,
ethylthio, propylthio, isopropylthio, n-butylthio, and the
like.
[0113] The term "alkylamino" refers to a group having the structure
--NHR' wherein R' is alkyl, as defined herein. The term
"dialkylamino" refers to a group having the structure
--N(R.sup.1).sub.2 where R.sup.1 is alkyl, as defined herein. The
term "aminoalkyl" refers to a group having the structure
NH.sub.2R'--, wherein R' is alkyl, as defined herein. In certain
embodiments, the alkyl group contains 1-20 aliphatic carbon atoms.
In certain other embodiments, the alkyl group contains 1-10
aliphatic carbon atoms. In yet other embodiments, the alkyl group
employed in the invention contains 1-8 aliphatic carbon atoms. In
still other embodiments, the alkyl group contains 1-6 aliphatic
carbon atoms. In yet other embodiments, the alkyl group contains
1-4 aliphatic carbon atoms. Examples of alkylamino include, but are
not limited to, methylamino, ethylamino, iso-propylamino and the
like.
[0114] Some examples of substituents of the above-described
aliphatic (and other) moieties of compounds of the invention
include, but are not limited to aliphatic; heteroaliphatic; aryl;
heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy;
heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio;
heteroarylthio; F; Cl; Br; I; --OH; --NO.sub.2; --CN; --CF.sub.3;
--CH.sub.2CF.sub.3; --CHCl.sub.2; --CH.sub.2OH;
--CH.sub.2CH.sub.2OH; --CH.sub.2NH.sub.2;
--CH.sub.2SO.sub.2CH.sub.3; --C(O)R.sub.x; --CO.sub.2(R.sub.x);
--CON(R.sub.x).sub.2; --OC(O)R.sub.x; --OCO.sub.2R.sub.x;
--OCON(R.sub.x).sub.2; --N(R.sub.x).sub.2; --S(O).sub.2R.sub.x;
--NR.sub.x(CO)R.sub.x wherein each occurrence of R.sub.x
independently includes, but is not limited to, aliphatic,
heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl,
wherein any of the aliphatic, heteroaliphatic, alkylaryl, or
alkylheteroaryl substituents described above and herein may be
substituted or unsubstituted, branched or unbranched, cyclic or
acyclic, and wherein any of the aryl or heteroaryl substituents
described above and herein may be substituted or unsubstituted.
Additional examples of generally applicable substituents are
illustrated by the specific embodiments shown in the Examples that
are described herein.
[0115] In general, the terms "aryl" and "heteroaryl", as used
herein, refer to stable mono- or polycyclic, heterocyclic,
polycyclic, and polyheterocyclic unsaturated moieties having
preferably 3-14 carbon atoms, each of which may be substituted or
unsubstituted. It will also be appreciated that aryl and heteroaryl
moieties, as defined herein may be attached via an aliphatic,
heteroaliphatic, alkyl or heteroalkyl moiety and thus also include
-(aliphatic)aryl, -(heteroaliphatic)aryl, -(aliphatic)heteroaryl,
-(heteroaliphatic)heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl,
-(heteroalkyl)aryl, and -heteroalkyl)heteroaryl moieties. Thus, as
used herein, the phrases "aryl or heteroaryl" and "aryl,
heteroaryl, (aliphatic)aryl, -(heteroaliphatic)aryl,
-(aliphatic)heteroaryl, -(heteroaliphatic)heteroaryl, -alkyl)aryl,
-(heteroalkyl)aryl, -(heteroalkyl)aryl, and
-heteroalkyl)heteroaryl" are interchangeable; Substituents include,
but are not limited to, any of the previously mentioned
substitutents, i.e., the substituents recited for aliphatic
moieties, or for other moieties as disclosed herein, resulting in
the formation of a stable compound. In certain embodiments of the
present invention, "aryl" refers to a mono- or bicyclic carbocyclic
ring system having one or two aromatic rings including, but not
limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl
and the like. In certain embodiments of the present invention, the
term "heteroaryl", as used herein, refers to a cyclic aromatic
radical having from five to ten ring atoms of which one ring atom
is selected from S, O and N; zero, one or two ring atoms are
additional heteroatoms independently selected from S, O and N; and
the remaining ring atoms are carbon, the radical being joined to
the rest of the molecule via any of the ring atoms, such as, for
example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,
imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,
oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and
the like.
[0116] It will be appreciated that aryl and heteroaryl groups
(including bicyclic aryl groups) can be unsubstituted or
substituted, wherein substitution includes replacement of one or
more of the hydrogen atoms thereon independently with any one or
more of the following moieties including, but not limited to:
aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl;
alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy;
alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I;
--OH; --NO.sub.2; --CN; --CF.sub.3; --CH.sub.2CF.sub.3;
--CHCl.sub.2; --CH.sub.2OH; --CH.sub.2CH.sub.2OH;
--CH.sub.2NH.sub.2; --CH.sub.2SO.sub.2CH.sub.3; --C(O)R.sub.x;
--CO.sub.2(R.sub.x); --CON(R.sub.x).sub.2; --OC(O)R.sub.x;
--OCO.sub.2R.sub.x; --OCON(R.sub.x).sub.2; --N(R.sub.x).sub.2;
--S(O).sub.2R.sub.x; --NR.sub.x(CO)R.sub.x wherein each occurrence
of R.sub.x independently includes, but is not limited to,
aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or
alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic,
alkylaryl, or alkylheteroaryl substituents described above and
herein may be substituted or unsubstituted, branched or unbranched,
cyclic or acyclic, and wherein any of the aryl or heteroaryl
substituents described above and herein may be substituted or
unsubstituted. Additional examples of generally applicable
substituents are illustrated by the specific embodiments shown in
the Examples that are described herein.
[0117] The term "cycloalkyl", as used herein, refers specifically
to groups having three to seven, preferably three to ten carbon
atoms. Suitable cycloalkyls include, but are not limited to
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
the like, which, as in the case of other aliphatic, heteroaliphatic
or hetercyclic moieties, may optionally be substituted with
substituents including, but not limited to aliphatic;
heteroaliphatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl;
alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio;
heteroalkylthio; heteroarylthio; F; Cl; Br; I; --OH; --NO.sub.2;
--CN; --CF.sub.3; --CH.sub.2CF.sub.3; --CHCl.sub.2; --CH.sub.2OH;
--CH.sub.2CH.sub.2OH; --CH.sub.2NH.sub.2;
--CH.sub.2SO.sub.2CH.sub.3; --C(O)R.sub.x; --CO.sub.2(R.sub.x);
--CON(R.sub.x).sub.2; --OC(O)R.sub.x; --OCO.sub.2R.sub.x;
--OCON(R.sub.x).sub.2; --N(R.sub.x).sub.2; --S(O).sub.2R.sub.x;
--NR.sub.x(CO)R.sub.x wherein each occurrence of R.sub.x
independently includes, but is not limited to, aliphatic,
heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl,
wherein any of the aliphatic, heteroaliphatic, alkylaryl, or
alkylheteroaryl substituents described above and herein may be
substituted or unsubstituted, branched or unbranched, cyclic or
acyclic, and wherein any of the aryl or heteroaryl substituents
described above and herein may be substituted or unsubstituted.
Additional examples of generally applicable substituents are
illustrated by the specific embodiments shown in the Examples that
are described herein.
[0118] The term "heteroaliphatic", as used herein, refers to
aliphatic moieties which contain one or more oxygen sulfur,
nitrogen, phosphorus or silicon atoms, e.g., in place of carbon
atoms. Heteroaliphatic moieties may be branched, unbranched, cyclic
or acyclic and include saturated and unsaturated heterocycles such
as morpholino, pyrrolidinyl, etc. In certain embodiments,
heteroaliphatic moieties are substituted by independent replacement
of one or more of the hydrogen atoms thereon with one or more
moieties including, but not limited to aliphatic; heteroaliphatic;
aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy;
heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio;
heteroarylthio; F; Cl; Br; I; --OH; --NO.sub.2; --CN; --CF.sub.3;
--CH.sub.2CF.sub.3; --CHCl.sub.2; --CH.sub.2OH;
--CH.sub.2CH.sub.2OH; --CH.sub.2NH.sub.2;
--CH.sub.2SO.sub.2CH.sub.3; --C(O)R.sub.x; --CO.sub.2(R.sub.x);
--CON(R.sub.x); --OC(O)R.sub.x; --OCO.sub.2R.sub.x;
--OCON(R.sub.x).sub.2; --N(R.sub.x).sub.2; --S(O).sub.2R.sub.x;
--NR.sub.x(CO)R.sub.x wherein each occurrence of R.sub.x
independently includes, but is not limited to, aliphatic,
heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl,
wherein any of the aliphatic, heteroaliphatic, alkylaryl, or
alkylheteroaryl substituents described above and herein may be
substituted or unsubstituted, branched or unbranched, cyclic or
acyclic, and wherein any of the aryl or heteroaryl substituents
described above and herein may be substituted or unsubstituted.
Additional examples of generally applicable substituents are
illustrated by the specific embodiments shown in the Examples that
are described herein.
[0119] The terms "halo", "halogen" and "halide" as used herein
refer to an atom selected from fluorine, chlorine, bromine and
iodine.
[0120] The term "haloalkyl" denotes an alkyl group, as defined
above, having one, two, or three halogen atoms attached thereto and
is exemplified by such groups as chloromethyl, bromoethyl,
trifluoromethyl, and the like.
[0121] The term "heterocycloalkyl" or "heterocycle", as used
herein, refers to a non-aromatic 5-, 6- or 7-membered ring or a
polycyclic group, including, but not limited to a bi- or tri-cyclic
group comprising fused six-membered rings having between one and
three heteroatoms independently selected from oxygen, sulfur and
nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds
and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen
and sulfur heteroatoms may be optionally be oxidized, (iii) the
nitrogen heteroatom may optionally be quaternized, and (iv) any of
the above heterocyclic rings may be fused to a benzene ring.
Representative heterocycles include, but are not limited to,
pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,
imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,
isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and
tetrahydrofuryl. In certain embodiments, a "substituted
heterocycloalkyl or heterocycle" group is utilized and as used
herein, refers to a heterocycloalkyl or heterocycle group, as
defined above, substituted by the independent replacement of one or
more of the hydrogen atoms thereon with but are not limited to
aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl;
alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy;
alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I;
--OH; --NO.sub.2; --CN; --CF.sub.3; --CH.sub.2CF.sub.3;
--CHCl.sub.2; --CH.sub.2OH; --CH.sub.2CH.sub.2OH;
--CH.sub.2NH.sub.2; --CH.sub.2SO.sub.2CH.sub.3; --C(O)R.sub.x;
--CO.sub.2(R.sub.x); --CON(R.sub.x).sub.2; --OC(O)R.sub.x;
--OCO.sub.2R.sub.x; --OCON(R.sub.x).sub.2; --N(R.sub.x).sub.2;
--S(O).sub.2R.sub.x; --NR.sub.x(CO)R.sub.x wherein each occurrence
of R.sub.x independently includes, but is not limited to,
aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or
alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic,
alkylaryl, or alkylheteroaryl substituents described above and
herein may be substituted or unsubstituted, branched or unbranched,
cyclic or acyclic, and wherein any of the aryl or heteroaryl
substitutents described above and herein may be substituted or
unsubstituted. Additional examples or generally applicable
substituents are illustrated by the specific embodiments shown in
the Examples which are described herein.
[0122] The term "carboxylic acid" as used herein refers to a group
of formula --COOH.
[0123] The term "carboxylic ester" as used herein refers to a group
of formula --CO.sub.2R.sub.x, wherein R.sub.x includes, but is not
limited to, aliphatic, heteroaliphatic, aryl, heteroaryl,
alkylaryl, or alkylheteroaryl, wherein any of the aliphatic,
heteroaliphatic, alkylaryl, or alkylheteroaryl substituents
described above and herein may be substituted or unsubstituted,
branched or unbranched, cyclic or acyclic, and wherein any of the
aryl or heteroaryl substituents described above and herein may be
substituted or unsubstituted.
[0124] The term "imine" as used herein refers to a group of formula
--CR.sub.y.dbd.NR.sub.x, wherein R.sub.x and R.sub.y are
independently hydrogen or an aliphatic, heteroaliphatic, aryl,
heteroaryl, alkylaryl, or alkylheteroaryl moiety, wherein any of
the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl
moieties described above and herein may be substituted or
unsubstituted, branched or unbranched, cyclic or acyclic, and
wherein any of the aryl or heteroaryl moieties described above and
herein may be substituted or unsubstituted.
[0125] The term "hydrazone" as used herein refers to a group of
formula --CR.sub.y.dbd.NHR.sub.x, wherein R.sub.x and R.sub.y are
independently hydrogen or an aliphatic, heteroaliphatic, aryl,
heteroaryl, alkylaryl, or alkylheteroaryl moiety, wherein any of
the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl
moieties described above and herein may be substituted or
unsubstituted, branched or unbranched, cyclic or acyclic, and
wherein any of the aryl or heteroaryl moieties described above and
herein may be substituted or unsubstituted.
[0126] The term "oxime" as used herein refers to a group of formula
--CR.sub.x.dbd.NOH, wherein R.sub.x includes, but is not limited
to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or
alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic,
alkylaryl, or alkylheteroaryl substituents described above and
herein may be substituted or unsubstituted, branched or unbranched,
cyclic or acyclic, and wherein any of the aryl or heteroaryl
substituents described above and herein may be substituted or
unsubstituted.
[0127] The term "acyl halide" as used herein refers to a group of
formula --(C.dbd.O)X, wherein X is a halide as defined above.
[0128] The term "amide" as used herein refers to a group of formula
--(C.dbd.O)NR.sub.xR.sub.y wherein R.sub.x and R.sub.y are
independently hydrogen or an aliphatic, heteroaliphatic, aryl,
heteroaryl, alkylaryl, or alkylheteroaryl moiety, wherein any of
the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl
moieties described above and herein may be substituted or
unsubstituted, branched or unbranched, cyclic or acyclic, and
wherein any of the aryl or heteroaryl moieties described above and
herein may be substituted or unsubstituted.
[0129] The term "acetal" as used herein refers to a group of
formula --CR.sub.z(OR.sub.x)(OR.sub.y) wherein R.sub.z includes,
but is not limited to, hydrogen or an aliphatic, heteroaliphatic,
aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety, R.sub.x and
R.sub.y are independently an aliphatic, heteroaliphatic, aryl,
heteroaryl, alkylaryl, or alkylheteroaryl moiety, wherein R.sub.x
and R.sub.y, when taken together, may form a heterocycloaliphatic
moiety comprising 5-7 atoms; and wherein any of the aliphatic,
heteroaliphatic, alkylaryl, or alkylheteroaryl moieties described
above and herein may be substituted or unsubstituted, branched or
unbranched, cyclic or acyclic, and wherein any of the aryl,
heteroaryl or heterocycloaliphatic moieties described above and
herein may be substituted or unsubstituted.
[0130] The term "anhydride" as used herein refers to a group of
formula --C(.dbd.O)OC(.dbd.O)R.sub.x wherein R.sub.x is an
aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or
alkylheteroaryl moiety, wherein any of the aliphatic,
heteroaliphatic, alkylaryl, or alkylheteroaryl moieties described
above and herein may be substituted or unsubstituted, branched or
unbranched, cyclic or acyclic, and wherein any of the aryl or
heteroaryl moieties described above and herein may be substituted
or unsubstituted.
[0131] 3) Synthetic Methodology
[0132] In recognition of the need for an efficient and practical
route to luminacin analogues, the present invention provides novel
synthetic methodologies for the synthesis of this class of
therapeutic agents. Although the synthesis of luminacin D (also
referred to herein as VD1207D) is described specifically herein
directly below (and in the Examples), it will be appreciated that
this methodology is generally applicable to the generation of
analogues and derivatives.
[0133] In one aspect, the present invention provides novel
luminacin analogs having formula (I) a described above and in
certain classes and subclasses herein. An overview of the synthesis
of the inventive compounds is provided below, as detailed in
Schemes 1-9, and in the Exemplification herein. It will be
appreciated that the methods as described herein can be applied to
each of the compounds as disclosed herein and equivalents thereof.
Additionally, the reagents and starting materials are well known to
those skilled in the art. Although the following schemes describe
certain exemplary compounds, it will be appreciated that the use of
alternate starting materials will yield other analogs of the
invention. For example, compounds are described below where R.sub.2
and R.sub.3 are taken together to form an epoxide; however, it will
be appreciated that alternate starting materials and/or
intermediates can be utilized to generate compounds where R.sub.2
and R.sub.3 are hydrogen or are taken together to form a
cyclopropyl ring, etc.
[0134] In certain embodiments, compounds as provided herein, are
prepared from a general advance intermediate, as depicted below
(20): 14
[0135] In certain embodiments, synthetic manipulations of general
advance intermediate 20 include two intramolecular cyclizations, as
depicted in Scheme 1. Intermediate 20 leads to the formation of
four diastereomers at C2' and C3', which can be separated by HPLC
and/or flash chromatography. Each diastereomer leads in turn to the
preparation of a luminacin analog through a series of synthetic
steps (see for example the synthesis of VD1207D depicted in Scheme
2). 1516 17
[0136] In certain embodiments, general advance intermediate 20 can
be synthesized from two components: an aromatic component, the
synthesis of which is depicted in Scheme 3 and is described in more
detail in examples herein, and an aldehyde component, the synthesis
of which is depicted in Scheme 4 and is described in more detail in
examples herein. As depicted in Scheme 5, and as described in more
detail in examples herein, these two components are coupled, and
subsequent oxidation to generate the general advance intermediate
(20) occurs. 18 19
[0137] It will be appreciated that each of the steps as described
above can be carried out using reagents and conditions as described
for the synthesis of VD1207D, or they may be modified using other
available reagents. For example, a variety of lactonisation
conditions, aromatic nucleus functionalization and asymmetric
epoxidation and/or hydroxylation conditions are well-known in the
art and can be utilized in the method of the invention. See,
generally, March 2001, "Advanced Organic Chemistry", 5th ed. John
Wiley and Sons, New York, N.Y.; and Larock 1990, "Comprehensive
Organic Transformations: A Guide to Functional Group Preparations",
2.sup.nd ed. VCH Publishers; the entire contents of which are
incorporated herein by reference.
[0138] As mentioned above, it will also be appreciated that each of
the components used in the synthesis of analogues can be
diversified either before synthesis or alternatively after the
construction of the luminacin construct. As used herein, the term
"diversifying" or "diversify" means reacting an inventive compound,
as defined herein, at one or more reactive sites to modify a
functional moiety or to add a functional moiety. For example, the
aromatic ring can be diversified (prior to or after reaction) to
either add functionality (e.g., where hydrogen is present, a
halogen or other functionality can be added) or to modify
functionality (e.g., where a hydroxyl group is present on the
aromatic ring, the aromatic ring can be diversified by reacting
with a reagent to protect the hydroxyl group, or to convert it into
an aliphatic or heteroaliphatic moiety). Described generally below
are a variety of schemes to assist the reader in the synthesis of a
variety of analogues, either by diversification of the intermediate
components or by diversification of the luminacin construct.
[0139] In certain embodiments, components used in the synthesis of
the core structure of the compounds of the invention are
diversified to give structurally related luminacin derivatives. In
certain embodiments, the invention encompasses compounds obtained
by varying the structure of the aromatic nucleus (A) or the
tetrahydropyran component (B) of the inventive compounds of formula
(I), as illustrated below: 20
[0140] In certain embodiments, the preparation of chemically
diverse derivatives may be achieved by diversifying a benzofuran
intermediate, such as that obtained by the synthetic method
detailed in Scheme 6. Examples of chemical transformations suitable
to achieve such derivatization include, but are not limited to,
hetero-Diels Alder, Aldol condensation, reductive amination,
metathesis, alkylation and Wittig-Horner-Emmons, as depicted in
Scheme 7. In addition, as described above, the aromatic ring can be
diversified (prior to or after reaction) to either add
functionality (e.g., where hydrogen is present, a halogen or other
functionality can be added) or to modify functionality (e.g., where
a hydroxyl group is present on the aromatic ring, the aromatic ring
can be diversified by reacting with a reagent to protect the
hydroxyl group, or to convert it into an aliphatic or
heteroaliphatic moiety). Subsequent oxidative cleavage of the
benzofuran nucleus, such as that depicted in Scheme 2 (last
synthetic step), would generate a library of structurally related
luminacin derivatives comprising an aryl moiety. 21 22
[0141] In other embodiments, the preparation of chemically diverse
derivatives may be achieved by diversifying the tetrahydropyran
component of the compounds of the invention, as depicted in Scheme
8. One skilled in the art will recognize that possible chemical
transformations suitable to achieve diversification of the
tetrahydropyran moiety are not limited to those depicted in Scheme
8. Rather, any suitable synthetic methods known in the art can be
used to achieve desired chemical transformations. 23
[0142] As detailed above, a variety of reactions can be utilized to
diversify the luminacin core structures after assembly of the
luminacin construct. Scheme 9 illustrates a few examples of such
reactions. A person of ordinary skill in the art will appreciate
that suitable chemical diversification methods are not limited to
those depicted in Scheme 9, and that any suitable synthetic methods
known in the art can be used to achieve desired chemical
transformations. 24
[0143] 4) Research Uses, Formulation and Administration
[0144] According to the present invention, the inventive compounds
may be assayed in any of the available assays known in the art for
identifying compounds having a pre-determined biological activity.
For example, the assay may be cellular or non-cellular, in vivo or
in vitro, high- or low-throughput format, etc. In certain exemplary
embodiments, the inventive compounds are tested in assays to
identify those compounds having angiogenesis inhibitory activity
and/or antiproliferative/anticanc- er activity.
[0145] Thus, in one aspect, compounds of this invention which are
of particular interest include those which:
[0146] exhibit cytotoxic or growth inhibitory effect on cancer cell
lines maintained in vitro or in animal studies using a
scientifically acceptable cancer cell xenograft model;
[0147] exhibit an antiangiogenic effect on solid tumors;
[0148] exhibit a favorable therapeutic profile (e.g., safety,
efficacy, and stability).
[0149] As detailed in the exemplification herein, in assays to
determine the ability of compounds to inhibit proliferation of
certain cell-lines, certain inventive compounds exhibited IC50
values less than 7 .mu.M. In other embodiments, exemplary compounds
exhibited IC50 values less than 1 .mu.M. In still other
embodiments, the cytotoxicity of certain compounds was evaluated in
vitro. Certain of these compounds exhibited IC50 values less than
15 .mu.M. In other embodiments, exemplary compounds exhibited IC50
values less than 30 .mu.M.
[0150] This invention also provides a pharmaceutical preparation
comprising at least one of the compounds as described above and
herein, or a pharmaceutically acceptable derivative thereof, which
compounds are capable of inhibiting the growth of or killing cancer
cells. The invention further provides a method for inhibiting tumor
growth and/or tumor metastasis.
[0151] As discussed above, certain of the compounds as described
herein act as inhibitors of tumor angiogenesis and thus are useful
in the treatment of cancer and in the inhibition of tumor growth
and in the killing of cancer cells. The invention further provides
a method for inhibiting tumor growth and/or tumor metastasis. The
method involves the administration of a therapeutically effective
amount of the compound or a pharmaceutically acceptable derivative
thereof to a subject (including, but not limited to a human or
animal) in need of it. In certain embodiments, the inventive
compounds are useful for the treatment of solid tumors. In still
other embodiments of interest, the inventive compounds are useful
for the treatment of glioblastoma, retinoblastoma, breast cancer,
cervical cancer, colon and rectal cancer, leukemia, lung cancer
(including, but not limited to small cell lung cancer), melanoma,
multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer,
pancreatic cancer, prostate cancer and gastric cancer.
[0152] Pharmaceutical Compositions
[0153] As discussed above this invention provides novel compounds
that have biological properties useful for the treatment of cancer.
Accordingly, in another aspect of the present invention,
pharmaceutical compositions are provided, which comprise any one of
the compounds described herein (or a prodrug, pharmaceutically
acceptable salt or other pharmaceutically acceptable derivative
thereof), and optionally comprise a pharmaceutically acceptable
carrier. In certain embodiments, these compositions optionally
further comprise one or more additional therapeutic agents.
Alternatively, a compound of this invention may be administered to
a patient in need thereof in combination with the administration of
one or more other therapeutic agents. For example, additional
therapeutic agents for conjoint administration or inclusion in a
pharmaceutical composition with a compound of this invention may be
a cytotoxic agent or anticancer agent approved for the treatment of
cancer, as discussed in more detail herein, or it may be any one of
a number of agents undergoing approval in the Food and Drug
Administration that ultimately obtain approval for the treatment of
an immune disorder or cancer. It will also be appreciated that
certain of the compounds of present invention can exist in free
form for treatment, or where appropriate, as a pharmaceutically
acceptable derivative thereof. According to the present invention,
a pharmaceutically acceptable derivative includes, but is not
limited to, pharmaceutically acceptable salts, esters, salts of
such esters, or a prodrug or other adduct or derivative of a
compound of this invention which upon administration to a patient
in need is capable of providing, directly or indirectly, a compound
as otherwise described herein, or a metabolite or residue
thereof.
[0154] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. Pharmaceutically acceptable salts of amines,
carboxylic acids, and other types of compounds, are well known in
the art. For example, S. M. Berge, et al. describe pharmaceutically
acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19
(1977), incorporated herein by reference. The salts can be prepared
in situ during the final isolation and purification of the
compounds of the invention, or separately by reacting a free base
or free acid function with a suitable reagent, as described
generally below. For example, a free base function can be reacted
with a suitable acid. Furthermore, where the compounds of the
invention carry an acidic moiety, suitable pharmaceutically
acceptable salts thereof may induce metal salts such as alkali
metal salts, e.g., sodium or potassium salts, and alkaline earth
metal salts, e.g., calcium or magnesium salts. Examples of
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid and
perchloric acid or with organic acids such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid or
malonic acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts include, when appropriate,
nontoxic ammonium, quaternary ammonium, and amine cations formed
using counterions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
[0155] Additionally, as used herein, the term "pharmaceutically
acceptable ester" refers to esters that hydrolyze in vivo and
include those that break down readily in the human body to leave
the parent compound or a salt thereof. Suitable ester groups
include, for example, those derived from pharmaceutically
acceptable aliphatic carboxylic acids, particularly alkanoic,
alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl
or alkenyl moeity advantageously has not more than 6 carbon atoms.
Examples of particular esters include formates, acetates,
propionates, butyrates, acrylates and ethylsuccinates.
[0156] Furthermore, the term "pharmaceutically acceptable prodrugs"
as used herein refers to those prodrugs of the compounds of the
present invention which are, within the scope of sound medical
judgment, suitable for use in contact with the issues of humans and
lower animals with undue toxicity, irritation, allergic response,
and the like, commensurate with a reasonable benefit/risk ratio,
and effective for their intended use, as well as the zwitterionic
forms, where possible, of the compounds of the invention. The term
"prodrug" refers to compounds that are rapidly transformed in vivo
to yield the parent compound of the above formula, for example by
hydrolysis in blood. A thorough discussion is provided in T.
Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14
of the A.C.S. Symposium Series, and in Edward B. Roche, ed.,
Bioreversible Carriers in Drug Design, American Pharmaceutical
Association and Pergamon Press, 1987, both of which are
incorporated herein by reference.
[0157] As described above, the pharmaceutical compositions of the
present invention additionally comprise a pharmaceutically
acceptable carrier, which, as used herein, includes any and all
solvents, diluents, or other liquid vehicle, dispersion or
suspension aids, surface active agents, isotonic agents, thickening
or emulsifying agents, preservatives, solid binders, lubricants and
the like, as suited to the particular dosage form desired.
Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W.
Martin (sack Publishing Co., Easton, Pa., 1980) discloses various
carriers used in formulating pharmaceutical compositions and known
techniques for the preparation thereof. Except insofar as any
conventional carrier medium is incompatible with the compounds of
the invention, such as by producing any undesirable biological
effect or otherwise interacting in a deleterious manner with any
other component(s) of the pharmaceutical composition, its use is
contemplated to be within the scope of this invention. Some
examples of materials which can serve as pharmaceutically
acceptable carriers include, but are not limited to, sugars such as
lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatine; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil, sesame oil; olive oil; corn oil and soybean
oil; glycols; such as propylene glycol; esters such as ethyl oleate
and ethyl laurate; agar; buffering agents such as magnesium
hydroxide and aluminum hydroxide; alginic acid; pyrogenfree water;
isotonic saline; Ringer's solution; ethyl alcohol, and phosphate
buffer solutions, as well as other non-toxic compatible lubricants
such as sodium lauryl sulfate and magnesium stearate, as well as
coloring agents, releasing agents, coating agents, sweetening,
flavoring and perfuming agents, preservatives and antioxidants can
also be present in the composition, according to the judgment of
the formulator.
[0158] Uses and Formulations of Compounds of the Invention
[0159] As described in more detail herein, in general, the present
invention provides compounds useful for the treatment of cancer.
Specifically, certain compounds of the invention have been shown to
inhibit the proliferation of human umbilical vein endothelial cells
(HUVEC) in vitro, as described in more detail herein, and are
useful for the treatment of cancer, including solid tumors.
[0160] As discussed above, compounds of the invention exhibit
anti-angiogenesis activity. As such, compounds of the invention are
particularly useful for the treatment of diseases and disorders
associated with increased angiogenesis, including, but not limited
to, cancer.
[0161] Angiogenesis, the proliferation and migration of endothelial
cells resulting in the formation of new blood vessels, is a
physiological component of reproductive functions, normal growth,
and development, as well as wound healing. Angiogenesis is also
observed in a variety of diseases such as diabetic retinopathy,
arthritis, and inflammation. In addition, angiogenesis has been
demonstrated to play important roles in the progression of cancer
by allowing tumor growth and facilitating formation of metastases.
The development of blood vessels within tumor tissues is closely
correlated with invasion and metastasis of cancer cells in breast
cancer, melanoma, lung cancer, prostate cancer and other cancers.
Consequently, inhibition of angiogenesis may lead to control of
tumor growth and metastasis. In addition, the use of angiogenesis
inhibitors presents certain advantages over standard chemotherapy
treatment in that angiogenesis inhibitors target dividing
endothelial cells rather than tumor cells. Thus, Anti-angiogenic
drugs are not likely to cause bone marrow suppression,
gastrointestinal symptoms, or hair loss; symptoms characteristic of
standard chemotherapy treatments. Furthermore, drug resistance is a
major problem with existing standard chemotherapy agents. This
stems from the fact that most cancer cells are genetically
unstable, are more prone to mutations and are therefore likely to
produce drug resistant cells. Since angiogenic drugs target normal
endothelial cells, which are not genetically unstable, drug
resistance is less likely to develop.
[0162] Thus, as described above, in one aspect of the invention,
methods for the treatment of cancer are provided comprising
administering a therapeutically effective amount of a compound of
formula (I), as described generally in classes and subclasses
herein, to a subject in need thereof. In certain embodiments of the
present invention a "therapeutically effective amount" of the
inventive compound or pharmaceutical composition is that amount
effective for detectable killing or inhibiting the growth of cancer
cells. Thus, the expression "effective amount" as used herein,
refers to a sufficient amount of agent to kill or inhibit the
growth of tumor cells. The exact amount required will vary from
subject to subject, depending on the species, age, and general
condition of the subject, the severity of the infection, the
particular anticancer agent, its mode of administration, and the
like. The compounds of the invention are preferably formulated in
dosage unit form for ease of administration and uniformity of
dosage. The expression "dosage unit form" as used herein refers to
a physically discrete unit of therapeutic agent appropriate for the
patient to be treated. It will be understood, however, that the
total daily usage of the compounds and compositions of the present
invention will be decided by the attending physician within the
scope of sound medical judgment. The specific therapeutically
effective dose level for any particular patient or organism will
depend upon a variety of factors including the disorder being
treated and the severity of the disorder; the activity of the
specific compound employed; the specific composition employed; the
age, body weight, general health, sex and diet of the patient; the
time of administration, route of administration, and rate of
excretion of the specific compound employed; the duration of the
treatment; drugs used in combination or coincidental with the
specific compound employed; and like factors well known in the
medical arts.
[0163] Furthermore, after formulation with an appropriate
pharmaceutically acceptable carrier in a desired dosage, the
pharmaceutical compositions of this invention can be administered
to humans and other animals orally, rectally, parenterally,
intracistemally, intravaginally, intraperitoneally, topically (as
by powders, ointments, or drops), bucally, as an oral or nasal
spray, or the like, depending on the severity of the infection
being treated. In certain embodiments, the compounds of the
invention may be administered at dosage levels of about 0.001 mg/kg
to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg, or from
about 0.1 mg/kg to about 10 mg/kg of subject body weight per day,
one or more times a day, to obtain the desired therapeutic effect.
It will also be appreciated that dosages smaller than 0.001 mg/kg
or greater than 50 mg/kg (for example 50-100 mg/kg) can be
administered to a subject. In certain embodiments, compounds are
administered orally or parenterally.
[0164] Liquid dosage forms for oral administration include, but are
not limited to, pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
[0165] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0166] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0167] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This may be accomplished by the use of a
liquid suspension or crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution that, in turn, may depend upon crystal
size and crystalline form. Alternatively, delayed absorption of a
parenterally administered drug form is accomplished by dissolving
or suspending the drug in an oil vehicle. Injectable depot forms
are made by forming microencapsule matrices of the drug in
biodegradable polymers such as polylactide-polyglycolide. Depending
upon the ratio of drug to polymer and the nature of the particular
polymer employed, the rate of drug release can be controlled.
Examples of other biodegradable polymers include (poly(orthoesters)
and poly(anhydrides). Depot injectable formulations are also
prepared by entrapping the drug in liposomes or microemulsions
which are compatible with body tissues.
[0168] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0169] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar--agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0170] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polethylene
glycols and the like.
[0171] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose and starch. Such dosage forms may also
comprise, as in normal practice, additional substances other than
inert diluents, e.g., tableting lubricants and other tableting aids
such as magnesium stearate and microcrystalline cellulose. In the
case of capsules, tablets and pills, the dosage forms may also
comprise buffering agents. They may optionally contain opacifying
agents and can also be of a composition that they release the
active ingredient(s) only, or preferentially, in a certain part of
the intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions which can be used include polymeric
substances and waxes.
[0172] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
are made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0173] As discussed above, in one aspect, the compounds of the
present invention are useful as anticancer agents, and thus may be
useful in the treatment of cancer, by effecting tumor cell death or
inhibiting the growth of tumor cells. In general, the inventive
anticancer agents are useful in the treatment of cancers and other
proliferative disorders, including, but not limited to
glioblastoma, retinoblastoms, breast cancer, cervical cancer, colon
and rectal cancer, leukemia, lung cancer (including, but not
limited to small cell lung cancer), melanoma, multiple myeloma,
non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate
cancer, and gastric cancer, to name a few.
[0174] It will also be appreciated that the compounds and
pharmaceutical compositions of the present invention can be
formulated and employed in combination therapies, that is, the
compounds and pharmaceutical compositions can be formulated with or
administered concurrently with, prior to, or subsequent to, one or
more other desired therapeutics or medical procedures. The
particular combination of therapies (therapeutics or procedures) to
employ in a combination regimen will take into account
compatibility of the desired therapeutics and/or procedures and the
desired therapeutic effect to be achieved. It will also be
appreciated that the therapies employed may achieve a desired
effect for the same disorder (for example, an inventive compound
may be administered concurrently with another anticancer agent), or
they may achieve different effects (e.g., control of any adverse
effects).
[0175] For example, other therapies or anticancer agents that may
be used in combination with the inventive anticancer agents of the
present invention include surgery, radiotherapy (in but a few
examples, .gamma.-radiation, neutron beam radiotherapy, electron
beam radiotherapy, proton therapy, brachytherapy, and systemic
radioactive isotopes, to name a few), endocrine therapy, biologic
response modifiers (interferons, interleukins, and tumor necrosis
factor (TNF) to name a few), hyperthermia and cryotherapy, agents
to attenuate any adverse effects (e.g., antiemetics), and other
approved chemotherapeutic drugs, including, but not limited to,
alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide,
Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine
antagonists and pyrimidine antagonists (6-Mercaptopurine,
5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons
(Vinblastine, Vincristine, Vinorelbine, Paclitaxel),
podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics
(Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine,
Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes
(Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and
Megestrol), to name a few. For a more comprehensive discussion of
updated cancer therapies see, http://www.nci.nih.gov/, a list of
the FDA approved oncology drugs at
http://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck
Manual, Seventeenth Ed. 1999, the entire contents of which are
hereby incorporated by reference.
[0176] In certain embodiments, the pharmaceutical compositions of
the present invention further comprise one or more additional
therapeutically active ingredients (e.g., chemotherapeutic and/or
palliative). For purposes of the invention, the term "Palliative"
refers to treatment that is focused on the relief of symptoms of a
disease and/or side effects of a therapeutic regimen, but is not
curative. For example, palliative treatment encompasses
painkillers, antinausea medications and anti-sickness drugs. In
addition, chemotherapy, radiotherapy and surgery can all be used
palliatively (that is, to reduce symptoms without going for cure;
e.g., for shrinking tumors and reducing pressure, bleeding, pain
and other symptoms of cancer).
Treatment Kits
[0177] In other embodiments, the present invention relates to a kit
for conveniently and effectively carrying out the methods in
accordance with the present invention. In general, the
pharmaceutical pack or kit comprises one or more containers filled
with one or more of the ingredients of the pharmaceutical
compositions of the invention. Such kits are especially suited for
the delivery of solid oral forms such as tablets or capsules. Such
a kit preferably includes a number of unit dosages, and may also
include a card having the dosages oriented in the order of their
intended use. If desired, a memory aid can be provided, for example
in the form of numbers, letters, or other markings or with a
calendar insert, designating the days in the treatment schedule in
which the dosages can be administered. Alternatively, placebo
dosages, or calcium dietary supplements, either in a form similar
to or distinct from the dosages of the pharmaceutical compositions,
can be included to provide a kit in which a dosage is taken every
day. Optionally associated with such container(s) can be a notice
in the form prescribed by a governmental agency regulating the
manufacture, use or sale of pharmaceutical products, which notice
reflects approval by the agency of manufacture, use or sale for
human administration.
Equivalents
[0178] The representative examples that follow are intended to help
illustrate the invention, and are not intended to, nor should they
be construed to, limit the scope of the invention. Indeed, various
modifications of the invention and many further embodiments
thereof, in addition to those shown and described herein, will
become apparent to those skilled in the art from the full contents
of this document, including the examples which follow and the
references to the scientific and patent literature cited herein. It
should further be appreciated that the contents of those cited
references are incorporated herein by reference to help illustrate
the state of the art.
[0179] The following examples contain important additional
information, exemplification and guidance that can be adapted to
the practice of this invention in its various embodiments and the
equivalents thereof.
Exemplification
[0180] The compounds of this invention and their preparation can be
understood further by the examples that illustrate some of the
processes by which these compounds are prepared or used. It will be
appreciated, however, that these examples do not limit the
invention. Variations of the invention, now known or further
developed, are considered to fall within the scope of the present
invention as described herein and as hereinafter claimed.
[0181] According to the present invention, any available techniques
can be used to make or prepare the inventive compounds or
compositions including them. For example, a variety of solution
phase synthetic methods such as those discussed in detail below may
be used. Alternatively or additionally, the inventive compounds may
be prepared using any of a variety combinatorial techniques,
parallel synthesis and/or solid phase synthetic methods known in
the art.
[0182] It will be appreciated as described below, that a variety of
inventive compounds can be synthesized according to the methods
described herein. The starting materials and reagents used in
preparing these compounds are either available from commercial
suppliers such as Aldrich Chemical Company (Milwaukee, Wis.),
Bachem (Torrance, Calif.), Sigma (St. Louis, Mo.), or are prepared
by methods well known to a person of ordinary skill in the art
following procedures described in such references as Fieser and
Fieser 1991, "Reagents for Organic Synthesis", vols 1-17, John
Wiley and Sons, New York, N.Y., 1991; Rodd 1989 "Chemistry of
Carbon Compounds", vols. 1-5 and supps, Elsevier Science
Publishers, 1989; "Organic Reactions", vols 1-40, John Wiley and
Sons, New York, N.Y., 1991; March 2001, "Advanced Organic
Chemistry", 5th ed. John Wiley and Sons, New York, N.Y.; and Larock
1990, "Comprehensive Organic Transformations: A Guide to Functional
Group Preparations", 2.sup.nd ed. VCH Publishers. These schemes are
merely illustrative of some methods by which the compounds of this
invention can be synthesized, and various modifications to these
schemes can be made and will be suggested to a person of ordinary
skill in the art having regard to this disclosure.
[0183] The starting materials, intermediates, and compounds of this
invention may be isolated and purified using conventional
techniques, including filtration, distillation, crystallization,
chromatography, and the like. They may be characterized using
conventional methods, including physical constants and spectral
data.
[0184] Certain exemplary compounds of the invention are listed
below and are referred to by compound number as indicated.
2 Ref. number Compound 805583 25 805615 26 805632 27 805633 28
805641 29 805640 30 805727 31 805728 32 805729 33 805730 34 805731
35 805732 36 805733 37 805754 38 805755 39 805757 40 805758 41
805759 42 805760 43 805828 44 805829 45 805866 46 805867 47 805868
48 805869 49 805870 50 805873 51 805888 52 805890 53 805892 54
805893 55 805907 56 805908 57 805909 58 805910 59 805926 60 805955
61 805956 62 806000 63 806001 64 806042 65 806043 66 806710 67
806711 68 806712 69 806768 70 806769 71 806770 72
[0185] 1) Experimental Procedures:
[0186] As described above, the present invention provides novel
luminacin analogs having formula (I) as described above and in
certain classes and subclasses herein. The synthesis of certain
exemplary compounds is described in detail below. It will be
appreciated that the methods as described herein can be applied to
each of the compounds as disclosed herein and equivalents thereof.
Additionally, certain regents and starting materials are well known
to those skilled in the art. Although the following examples
describe certain exemplary compounds, it will be appreciated that
the use of alternate starting materials will readily yield other
analogues encompassed by the invention.
[0187] General Reaction Procedures:
[0188] Unless mentioned specifically, reaction mixtures were
stirred using a magnetically driven stirrer bar. An inert
atmosphere refers to either dry argon or dry nitrogen. Reactions
were monitored either by thin layer chromatography, or by proton
nuclear magnetic resonance, of a suitably worked up sample of the
reaction mixture.
[0189] General Work Up Procedures:
[0190] Unless mentioned specifically, reaction mixtures were cooled
to room temperature or below then quenched, when necessary, with
either water or a saturated aqueous solution of ammonium chloride.
Desired products were extracted by partitioning between water and a
suitable water-immiscible solvent (eg. ethyl acetate,
dichloromethane, diethyl ether). The desired product containing
extracts were washed appropriately with water followed by a
saturated solution of brine. On occasions where the product
containing extract was deemed to contain residual oxidants, the
extract was washed with a 10% solution of sodium sulphite in
saturated aqueous sodium bicarbonate solution, prior to the
aforementioned washing procedure. On occasions where the product
containing extract was deemed to contain residual acids, the
extract was washed with saturated aqueous sodium bicarbonate
solution, prior to the aforementioned washing procedure (except in
those cases where the desired product itself had acidic character).
On occasions where the product containing extract was deemed to
contain residual bases, the extract was washed with 10% aqueous
citric acid solution, prior to the aforementioned washing procedure
(except in those cases where the desired product itself had basic
character). Post washing, the desired product containing extracts
were dried over anhydrous magnesium sulphate, then filtered. The
crude products were then isolated by removal of solvent(s) by
rotary evaporation under reduced pressure, at an appropriate
temperature (generally less than 45.degree. C.).
[0191] On occasions where triphenylphosphine oxide was a major
byproduct of the reaction, the reaction mixture was added directly
to a large volume of well-stirred hexane. The resultant precipitate
of triphenylphosphine oxide was removed by filtration and the
filtrate processed in the usual manner.
[0192] General Purification Procedures:
[0193] Unless mentioned specifically, chromatographic purification
refers to flash column chromatography on silica, using a single
solvent or mixed solvent as eluent. Suitably purified desired
product containing elutes were combined and concentrated under
reduced pressure at an appropriate temperature (generally less than
45.degree. C.) to constant mass. Final compounds were dissolved in
50% aqueous acetonitrile, filtered and transferred to vials, then
freeze-dried under high vacuum before submission for biological
testing.
EXAMPLE 1
Preparation of Compound VD-1207D
[0194] 73
[0195] Preparation of Compound 3: 74
[0196] 2,2-Dimethyl-5-Hydroxy-4-oxo-benzo-1,4-Dioxin (100 g, 0.515
mol) was dissolved in 500 mL of DMF. To this solution was added
methallyl chloride (75 mL, 0.760 mol), NaI (10 g, 0.066 mol), and
K.sub.2CO.sub.3 (100 g, 0.724 mol) and the solution was stirred
with a mechanical stirrer for 7 hours. At this point, IL (10 vol)
of H.sub.2O was added dopwise keeping the reaction temperature
below 33.degree. C. The reaction was then cooled to 5.degree. C.
and the product precipitated. The white solid was collected by
filtration and then redissolved in IPA (300 mL, 3 vol) by heating
to approx. 67.degree. C. Reaction cooled to approx 49.degree. C.
and H.sub.2O (300 ml, 3 vol) was added to precipitate desired
product (109.8 g, 85.8%).
[0197] Preparation of Compound 4: 75
[0198] Compound 3 (100 g, 0.403 mol) was added to a 3-neck round
bottom flask equipped with a N.sub.2 outlet, JKEM temperature
control, mechanical stirrer and heated to 210.degree. C. The
product was used with out purification in the next reaction.
[0199] Preparation of Compound 5: 76
[0200] The unpurified product 4 was then dissolved into reagent
grade alcohol. Pd/C 10% by wt was then added and placed under 1 atm
of H.sub.2. After reaction is complete, Pd/C is filtered off
through a pad of celite. After rinsing the filter cake with reagent
grade alcohol there was approximately 600 mL of the filtrate. To
this was added approximately 150 mL of H.sub.2O. At this point, the
desired product precipitates from solution. The precipitate was
collected and dried to obtain a white solid. (15 g, 74%, two
steps).
[0201] Preparation of Compound 6: 77
[0202] Compound 5 (11 g, 44 mmol) was dissolved in DMF (44 mL) at
RT followed by the addition of K.sub.2CO.sub.3 (12 g, 88 mmol). To
this stirred solution was added BnBr (11 g, 66 mmol) and stirred
for 12 hours. The reaction mixture was then filtered through
celite, washed with CH.sub.2Cl.sub.2, and the organics
concentrated. The crude oil was then purified by passing through a
plug of silica and eluting with 20:1 hexanes:EtOAc. (14.8 g,
99%).
[0203] Preparation of Compound 7: 78
[0204] Compound 6 (3 g, 8.82 mmol) was dissolved in 30 mL of THF
and cooled to 0.degree. C. LAH (336 mg, 8.82 mmol) was then added
portion wise. Reaction progress was monitored by TLC analysis and
was complete after 1 hour. Reaction was quenched with 1N HCl
followed by Rochell's salt and stirred for 1 hour. The aqueous
layer was then washed with EtOAc (3.times.100 mL) and the combined
organic layers dried over Mg.sub.2SO.sub.4. The crude material was
then purified by flash column chromatography and eluted with 3:1
Hexanes:EtOAc to obtain a clear colorless oil which solidified upon
standing (1.95 g, 77%).
[0205] Preparation of Compound 8: 79
[0206] Compound 7 (4.54 g, 15.88 mmol) was dissolved in 80 mL of
CH.sub.2Cl.sub.2 and cooled to 0.degree. C. To this was added NIS
(3.57 g, 15.88 mmol) and reaction allowed to warm to RT. Reaction
was complete after 2 hours and quenched by addition of
Na.sub.2HCO.sub.3 and the 1N Na.sub.2SO.sub.3. The aqueous layers
were washed with CH.sub.2Cl.sub.2 (3.times.50 MnL) and the combined
organics dried over MgSO.sub.4. The crude product was then purified
by flash column chromatography and eluted with 5:1 hexanes:EtOAc.
(3.78 g, 58%).
[0207] Preparation of 3-Benzyloxy-1-propanal (9): 80
[0208] Oxallyl Chloride (102.6 mL, 205.14 mmol) was dissolved in
600 mL of CH.sub.2Cl.sub.2 and cooled to -78.degree. C. DMSO (25.5
mL, 394.5 mmol) was then added through an addition funnel followed
by 3-benzyloxy-1-propanol (25 mL, 157.8 mmol) dissolved in 200 mL
of CH.sub.2Cl.sub.2, then Et.sub.3N (109.9 mL, 789 mmol). The
reaction mixture was then allowed to warm to room temp and left to
stir overnight. Reaction mixture was then diluted with approx. 600
mL of water and the organic layer separated. The aqueous layer was
then washed with 2.times.300 mL of CH.sub.2Cl.sub.2. Organics were
combined, dried over MgSO.sub.4, and concentrated. The crude oil
was purified by flash chromatography eluting with Hex/EtOAc
(6/1).
[0209] Preparation of E and Z- (10): 81
[0210] Sodium hydride 60% (39.25 g, 981 mmol) was dissolved in 750
ml of THF in a 3 necked round bottom flask, cooled to 0.degree. C.
and placed under a nitrogen atmosphere. Triethyl phosphonoacetate
(200 g, 892 mmol) diluted in 500 ml of THF was added via cannula
and the reaction mixture was stirred for 20 minutes. Bromine
(156.83 g, 981 mmol) was added dropwise and the reaction mixture
was stirred for 10 minutes. Sodium hydride 60% (39.25 g, 981 mmol)
was added portionwise and the reaction mixture was stirred for 30
min at 0.degree. C. After letting the reaction warm to room
temperature, propanaldehyde (981 mmol) was dissolved in 200 ml of
THF and added dropwise to the reaction mixture and stirred for 16
hrs at room temperature. Reaction was quenched with brine (700 ml)
and the aqueous phase washed with ethyl acetate (3.times.500 ml).
The combined organics were dried over magnesium sulfate, filtered
and then concentrated. Purification by column chromatography (100:1
hexanes:ethyl acetate) afforded 289 g (97%) of a 50/50 E, Z mixture
of 10 which could be partially separated.
[0211] Preparation of Compound 11 82
[0212] Aldehyde 9 (39.36 g, 0.24 mol) was combined with vinyl
bromide 10 (90.7 g, 0.47 mol) and placed under an atmosphere of
nitrogen. The mixture was then dissolved in 2.3 L of DMF and
secured in the fume hood. Ni/Cr (0.5% in Ni, 88 g, 0.72 mol) was
then weighed into three batches approx. 29.3 g in the dry box. The
catalyst was removed from the dry box and added to the rxn mixture
in the fume hood in three batches (careful of exotherm). Rxn left
to stir overnight. TLC analysis indicated that all aldehyde was
consumed. At this point, the rxn was quenched with sodium serinate
solution approx. 1 L and stirred in the presence of MTBE for one
hour. Organics were separated and the aqueous layer washed with
MTBE 3.times.400 mL. Organic layers were combine, dried over
Na.sub.2SO.sub.4, and concentrated. The Crude green oil was
purified by sillica gel chromatography eluting with 6:1
Hexanes:Ethyl acetate to obtain 29.8 g of 11 (44% based on
aldehyde) as a single olefin isomer.
[0213] Preparation of Compound 12 83
[0214] Alyllic alcohol 11 (19.76 g, 67.7 mmol) was dissolved in 340
mL of CH.sub.2Cl.sub.2 followed by the addition of 20 g of 4 .ANG.
MS. The reaction was then cooled down to -5.degree. C. by
submerging into a cryocool bath. At this time, Ti(OiPr).sub.4 (4.03
mL, 13.53 mmol) was then added (solution turned yellow) followed by
the addition of t-butylhydroperoxide (5-6 M in nonane, 11.33 ml,
62.32 mmol) and left to stir overnight at -5.degree. C. Reaction
was still not complete after 12 hours and 10 g of 4 .ANG. MS, 2 mL
if Ti(OiPr).sub.4, and 10 mL of t-butylhydroperoxide were added.
The reaction was complete after I additional hour. The reaction was
quenched by the addition of Sat. sodium sulfite (400 ml). Celite
was then added to the mixture, stirred for 10 min, and filtered
through a pad of celite. The pad was washed thoroughly with 300 mL
of CH.sub.2Cl.sub.2 and then the aqueous layers washed with
CH.sub.2Cl.sub.2. The organics were then dried over
Na.sub.2SO.sub.4 and concentrated to obtain a slightly yellow oil
which was purified by sillica gel (650 g) chromatography eluting
with 2:1 MTBE:Hexanes to obtain 14.3 g (68%) of 12.
[0215] Preparation of Compound 13 84
[0216] The epoxy alcohol 12 (4.64 g, 15 mmol) was dissolved in
CH.sub.2Cl.sub.2 (100 ml) at room temperature under nitrogen.
Triphenyl phosphine (4.34 g, 16.57 mmol) was added followed by
p-nitrobenzoic acid (2.77 g, 16.57 mmol). DIAD (3.26 ml, 16.57
mmol) was added dropwise. After a couple of hours, the reaction was
quenched with H.sub.2O and the aqueous layer washed with EtOAc. The
organic layer was dried over Na.sub.2SO.sub.4 and concentrated to
obtain a yellow oil. The crude material was purified by silica gel
column, eluting with MTBE/hexanes (1:3). Fractions containing
desired product were combined and concentrated to give a white
solid with a 34% yield.
[0217] The p-nitrobenzoate (2.12 g, 4.64 mmol) was dissolved in
EtOH (10 ml) and K.sub.2CO.sub.3 (1.92 g, 13.93 mmol) was added.
The suspension was stirred at room temperature for 2 hours. EtOH
was removed, H.sub.2O added and the aqueous layer washed with
EtOAc. The organics were dried over Na.sub.2SO.sub.4 and
concentrated to obtain a yellow oil. The crude material was
purified by silica gel column, eluting with MTBE/hexan (1:3).
Fractions containing desired product were combined to give a
colorless oil with a 65% yield.
[0218] Preparation of Compound 14 85
[0219] Compound 13 (6.05 g, 20.6 mmol) was dissolved in 100 ml of
CH.sub.2Cl.sub.2 and then cooled to 0.degree. C. Et.sub.3N (3.73
ml, 26.78 mmol) was then added followed by TBSOTf (5.2 ml, 22.66
mmol). The reaction was complete in 30 min. Quenched with MeOH (20
ml), concentrated, and then the crude oil was purified by sillica
gel chromatography eluting with 6:1 hexanes:EtOAc to obtain 7.31 g
of 14 (87%). Alternatively, 13 (0.83 g, 2.82 mmol) was dissolved in
DMF at RT, followed by the addition of TBSCl (0.62 g, 4.11 mmol)
and imidizole (0.36 g, 5.29 mmol). Reaction mixture was stirred
overnight. DMF was removed in vaccuo and the oil redisolved in
H.sub.2O. The aqueous layer was then washed with EtOAc (3.times.20
ml) and dried over Na.sub.2SO.sub.4. The crude oil was purified by
silica gel chromatography eluting with 6:1 hexanes:EtOAc to obtain
0.93 g of 14 (82%).
[0220] Preparation of Compound 15 86
[0221] Compound 14 (911 mg, 2.16 mmol) was dissolved in 12 ml of
THF at RT. Pd(OH).sub.2/C 20% (45 mg, 5%/wt) was then added and
reaction vessel placed under 1 atm of H.sub.2 and stirred at RT for
4 hrs. At this point, another 5%/wt of Pd(OH).sub.2/C was added and
reaction was complete after an additional 2 hrs. The catalyst was
removed by filtration through a pad of celite and rinsed with
EtOAc. Obtained 717 mg (100%) of 14 as a crude oil and used
directly in the next reaction. Note: deprotection with Pd/C was
unsuccessful.
[0222] Preparation of Compound 16 87
[0223] (COCl).sub.2 (1.73 ml, 3.46 mmol) was dissolved in 6 ml of
CH.sub.2Cl.sub.2 and cooled to -78.degree. C. followed by the
addition of DMSO (460 ml, 6.48 mmol) dropwise. The crude oil 15
(717 mg, 2.16 mmol) in 4 ml of CH.sub.2Cl.sub.2 (rinse 2 ml) was
then added dropwise followed by Et.sub.3N. Reaction was stirred at
-78.degree. C. for 5 min and then warmed to RT and stirred for 30
min. Reaction was quenched with H.sub.2O and the aqueous layer
washed 3.times.30 ml with CH.sub.2Cl.sub.2. The combined organics
were then dried with Na.sub.2SO.sub.4 and then concentrated. The
crude oil was then purified by silica gel chromatography and eluted
with 10:1, 6:1, 4:1, 3:1 hexanes:EtOAc to obtain 612 mg (86% for 2
steps).
[0224] Preparation of Compound 17 88
[0225] Procedure A: Commercially available 2-hexyne-1-ol (28.1 g,
286.32 mmol) was dissolved in 600 ml of THF in a 3 L flask.
PdCl2(Ph.sub.3P).sub.2 (4.02 g, 5.73 mmol) was then added followed
by the dropwise addition of nBu.sub.3SnH via addition funnel.
Reaction mixture was then stirred overnight and complete by TLC
annalysis. 500 ml of NaHCO.sub.3 was then added to quench the
reaction. THF was stripped down and the aqueous layer washed with
3.times.500 ml EtOAc. The organics were combined, dried over
anhydrous MgSO.sub.4 and concentrated. The crude oil was purified
by silica gel chromatography eluting with 50:1, 20:1, 10:1, 3:1
hexanes:ethyl acetate to obtain 54.3 g (39%) of the undesired
E-isomer and 16.6 g (15%) of the desired Z-isomer. The Z-isomer
(16.5 g, 42.4 mmol) was then dissolved in 150 ml of
CH.sub.2Cl.sub.2 and cooled to 0.degree. C. 12 was then dissolved
in 300 ml of CH.sub.2Cl.sub.2 and added dropwise until a red color
persisted. The CH.sub.2Cl.sub.2 was then removed in vacuo and the
crude oil purified by silica gel chromatography eluting with 10:1,
8:1, 5:1, 3:1 hexanes:EtOAc. The compound was then washed with
sodiumthiosulfate to remove any excess iodine. Concentration of the
organics provided 8.5 g (95%) of the desired Z-vinyl iodide.
[0226] Preparation of Compound 18 89
[0227] Compound 8 (3 g, 7.28 mmol) was dissolved in 40 mL of
CH.sub.3CN followed by the addition of 17 (2.5 g, 8.74 mmol) and
K.sub.2CO.sub.3 (1.2 g, 8.74 mmol) and stirred at RT for 12 hours.
Reaction complete by TLC and quenched with H.sub.2O. The aqueous
layers were washed with EtOAc (3.times.50 mL) and the combined
organics dried over Mg.sub.2SO.sub.4. The organics were
concentrated to obtain a yellow oil which was then dissolved in 50
mL of DMF. To this solution was added imidizole (1.12 g, 16.5
mmol), TBSCl (1.65 g, 11.0 mmol) and stirred at RT overnight. DMF
was then removed on high vacuum, H.sub.2O added, and aqueous layer
washed with EtOAc (3.times.50 mL). Crude product was then purified
by flash column chromatography and eluted with 8:1 hexanes:EtoAc.
(78% two steps).
[0228] Preparation of Compound 19 90
[0229] Aldehyde 16 (612 mg, 1.86 mmol) and vinyl iodide 18 (1.63 g,
2.23 mmol) were combined in a 25 ml round bottom flask with a stir
bar. O.sub.2 was removed by placing under a vacuum and purging with
N.sub.2 three times. The reaction vessel was then brought into the
dry box where DMSO (10 ml) was added followed by the slow and
portion wise addition of Ni/Cr (0.5% Ni, 912 mg, 7.42 mmol) with
rapid stirring of the reaction mixture. The reaction vessel was
then removed from the dry box, secured in the fume hood, and
stirred for 4 hrs. Reaction mixture was then poured into 100 ml of
Sat. NH.sub.4Cl and stirred overnight with 50 ml of MTBE. The
aqueous layer was then washed 3.times.50 ml of MTBE and the
organics combined, washed with Brine 100 ml, and dried over
Na.sub.2SO.sub.4. The crude oil was purified by silica gel
chromatography and eluted with 10:1, 6:1, 3:1 to obtain 1.27 g of
19 (73%) as a mixture of alcohol diastereomers.
[0230] Preparation of Compound 20 91
[0231] Allylic alcohol 19 (808 mg, 0.861 mmol) was dissolved in 5.7
mL of CH.sub.2Cl.sub.2 followed by the addition of 4 .ANG. MS (1.2
g, oven dried). To this stirred solution was added NMO (110 mg,
0.947 mmol) followed by TPAP (30 mg, 0.086 mmol) and stirred at RT.
The reaction was complete by TLC analysis in 1 hour. The molecular
sieves were filtered away by passing through a pad of celite and
washing the pad with Ethyl acetate. The organics were concentrated
and passed through a plug of silica gel, eluting with 3:1
Hexanes:EtOAc. Obtained 690 mg (85% yield) of a clear colorless
liquid.
[0232] Preparation of Compounds 21a and 21b 92
[0233] Ketone 20 (690 mg, 0.737 mmol) was dissolved in 7.5 mL of
1:1 CH.sub.3CN:THF at RT. To this stirred solution was added
Et.sub.3N (205 mL, 1.47 mmol) followed by Pd(dba).sub.2 chloroform
adduct (38 mg, 0.37 mmol) and the reaction was heated to 70.degree.
C. The reaction progress was monitored by Mass spectrometry and
completed after 5.5 hours. The reaction was cooled to RT, filtered
through a pad of celite, concentrated, and purified by silica gel
chromatography eluting with 7:1 Hexanes:MTBE. Obtained 536 mg (90%)
as a clear colorless oil and a 1:1 mixture of propyl isomers.
Separation of the propyl isomers was accomplished using a Dynamax
Prep HPLC (77 mm column) eluting with 5% MTBE in hexanes, flow rate
of 60 mL/min., monitoring at 254.lambda.. Higher R.sub.f spot was
assigned as 21a, lower R.sub.f spot was assigned as 21b. 21a can be
equilibrated to 21b by the following procedure: 21a (3.8 g, 4.7
mmol) was dissolved in toluene (10 mL) and
1,8-diazabicyclo[5.4.0]undec-7-ene (143 mg, 0.97 mmol) was added.
Stir at RT for 5 hours and quenched with H.sub.2O (1 mL). The
mixture was extracted with EtOAc and the organic layer was dried
over MgSO.sub.4, filtered and concentrated to give a clear oil
which was a 1:1 mixture of 21a and 21b. This mixture was separated
and the pure 21b was obtained (1.7 g) in 45% yield.
[0234] Preparation of Compounds 22a and 22b 93
[0235] Ketone 21a higher Rf (64 2 mg, 0.795 mmol) was dissolved in
10 mL of MeOH and cooled to 0.degree. C. To this stirred solution
was added NaBH.sub.4 (30 mg, 0.795 mmol). The reaction was
monitored by TLC analysis and complete after 1.5 hours. The
reaction mixture was then diluted with water and CH.sub.2Cl.sub.2
and stirred for 1 hour. Aqueous layer was then washed with
CH.sub.2Cl.sub.2, EtOAc, and MTBE. The organics were then combined,
dried over Na.sub.2SO.sub.4 and concentrated. The C3' isomers were
separable by Preparative HPLC. Conditions: Dynamax Prep HPLC, 77 mm
column, 10% MTBE in hexanes, flow rate of 120 mL/min, 254.lambda.,
175 mg/2 mL injection. Obtained 314 mg of the higher R.sub.f
diastereomer (22a) and 256 mg of the lower R.sub.f diastereomer
(22b) (Ratio 1.2:1, 88% combined yield).
[0236] Preparation of Compounds 22c and 22d
[0237] 22c and 22d: Ketone 22b lower Rf (500 mg, 0.623 mmol) was
dissolved in 5 mL of MeOH and cooled to 0.degree. C. To this
stirred solution was added NaBH (23 mg, 0.623 mmol) and stirred at
0.degree. C. for 1 hr. Reaction was quenched with water, the
aqueous layers washed with EtOAc, and the organics dried over
Na.sub.2SO.sub.4. The crude oil (ratio 2.1:1 mixture of C3'
diastereomers) was purified by silica gel chromatography eluting
with 8:1 Hexanes:MTBE to obtain the higher R.sub.f diastereomer 22c
(284 mg, 57%) followed by 1:1 hexanes:MTBE to remove the lower
R.sub.f diastereomer 22d (134 mg, 27%) for an overall yield of
84%.
[0238] Preparation of Compound 23d 94
[0239] Ester 22d (134 mg, 0.166 mmol) was dissolved into 13 mL of
THF followed by the addition of 3.3 mL of 2M LiOH. The reaction
vessel was then equipped with a reflux condenser and heated to
50.degree. C. The reaction was complete by TLC after 3 hours and
allowed to cool to RT. The solution was neutralized with 1N HCl and
the aqueous layers washed with EtOAc (3.times.10 mL). The organic
layers were dried over Na.sub.2SO.sub.4 and concentrated to obtain
126 mg (97%) of a clear oil. The material was then used in the next
reaction without any purification. (CJ-619-106). Note: The acid 23
is not stable and should not be stored. Upon storing compound in
the freezer over the weekend one TBS group fell off.
[0240] Preparation of Compound 24d 95
[0241] Acid 23d (112 mg, 0.144 mmol) was dissolved in 15 mL of
toluene followed by the addition of 2,4,6-tricholobenzoylchloride
(25 .mu.L, 0.158 mmol) and Et.sub.3N (60 .mu.L, 0.432 mmol). The
reaction was stirred at RT for 20 min. before the addition of DMAP
(19 mg, 0.158 mmol) which produces a cloudy white suspension. The
reaction was complete by TLC analysis after 30 min and quenched
with H.sub.2O. The aqueous layers were then washed with EtOAc,
dried over Na.sub.2SO.sub.4 and concentrated. The crude oil wass
purified by passing through a plug of silica eluting with 6:1
hexanes:EtOAc to obtain 109 mg (99%) of a colorless oil.
[0242] Preparation of Compound 25d 96
[0243] Lactone 24d (49 mg, 0.064 mmol) was dissolved in 1 mL of
toluene and cooled to -78.degree. C. To this stirred solution was
added Dibal (1M in CH.sub.2Cl.sub.2, 128 mL, 0.128 mmol). The
reaction progress was monitored by mass spec. After 15 min,
reaction was not complete. At this time 0.5 equiv. of Dibal was
added. After 5 additional minutes, the reaction was complete.
Quenched with Rochell's salt, extracted with EtOAc, and dried over
Na.sub.2SO.sub.4 to obtain 50 mg of a colorless oil which was used
without purification is the next reaction.
[0244] Preparation of Compound 26d 97
[0245] Lactol 25d (50 mg, 0.64 mmol) was dissolved in 3 mL of EtOH
followed by the addition W-2 Raney Ni (spatula tip, weight unknown
comes in a solution in H.sub.2O) at RT. Reaction progress was
monitored by mass spec and is complete after 1 hour. The reaction
was then filtered through celite and washed with CH.sub.2Cl.sub.2
and H.sub.2O (careful not to let Raney Ni go dry). The aqueous
layer is then washed with CH.sub.2Cl.sub.2, the organics dried over
Na.sub.2SO.sub.4, and concentrated to obtain 33 mg (76%) of a
colorless oil.
[0246] Preparation of Compound 27d 98
[0247] Phenol 26d (32 mg, 0.048 mmol) was dissolved in 1 mL of THF
and cooled to 0.degree. C. TBAF (1M in THF, 122 .mu.L, 0.122 mmol)
was then added and after 45 min only the monodeprotected mass was
detected by mass spec. Reaction was allowed to warm to RT and
complete after 4.5 hours. Quenched with NH.sub.4Cl, aqueous layers
washed with EtOAc, and the combined organics dried over
Na.sub.2SO.sub.4. The crude oil was used without further
purification in the next reaction.
[0248] Preparation of Compound 28d 99
[0249] Triol 27d (0.048 mmol) was dissolved in 5 mL of CH.sub.3CN.
To this solution was added solid K.sub.2CO.sub.3 (30 mg, 0.22 mmol)
and cinammyl bromide (11 mg, 0.058 mmol) and stirred at RT for 2
days. Reaction is monitored by TLC and mass spec. Quenched with
H.sub.2O, aqueous layers washed with EtOAc, and the combined
organic layers dried over Na.sub.2SO.sub.4. The crude oil was
purified by passing through a pipet column eluting with 2:1
MTBE:Hexanes to obtain 17 mg (63% for the two steps
26d.fwdarw.28d).
[0250] Preparation of Compound 29d 100
[0251] Lactol 28d (7 mg, 0.12 mmol) was dissolved in 3 mL of
CH.sub.2Cl.sub.2 followed by the addition of MnO.sub.2 (77 mg) at
RT. Reaction progress monitored by TLC and after 1.5 hours, 8 mg
more of MnO.sub.2 was added. After 30 additional minutes, the
reaction was complete. The reaction was then filtered through a
plug of celite, washed with CH.sub.2Cl.sub.2, and concentrated. The
crude material was used without purification in the next
reaction.
[0252] Preparation of Compound 30d 101
[0253] Aldehyde 29d (0.12 mmol) was dissolved in 2 mL of
EtOH:H.sub.2O (5:1) followed by Et.sub.3N (75 .mu.L, 0.54 mmol),
PPh.sub.3 (4 mg, 0.15 mmol), Pd(OAc).sub.2 (3 mg, 0.013 mmol), and
formic acid (15 .mu.L). The reaction was monitored by TLC and
complete in 20 min. The reaction was neutralized with NaHCO.sub.3,
the aqueous layers washed with EtOAc, and then concentrated. The
crude material was purified by Prep TLC (plates pre-eluted with
MTBE) eluting with 2:1 MTBE:Hexanes. Obtained 0.97 mg of a yellow
solid after lyophilization.
[0254] Preparation of VD-1207D 102
[0255] Benzofuran 30d (0.012 mmol) was dissolved in 2 mL of
CH.sub.2Cl.sub.2 and cooled to -78.degree. C. 03 is then bubbled in
the reaction mixture for 20 seconds. By mass spec and TLC analysis,
there was no starting material and the mass spec showed M-H for
VD-1207D. At this time, 0.2 mL of Me.sub.2S is added at -78.degree.
C. and then allowed to warm slowly to RT and stirred for 30
minutes. The reaction was then concentrated. Purification was
accomplished by Prep TLC (plate pre-eluted with acetone) eluting
with 7:3 Hexanes:Acetone or HPLC (ODS column, CH.sub.3CN 50%,
KH.sub.2PO.sub.4 buffer (pH=3.5) 50%, 1 mL/min.).
[0256] Note: Chiral HPLC Resolution
[0257] 23d and 25d can be resolved by Chiral HPLC allowing access
to each enantiomer of VD-1207D and subsequent analogs through the
procedures described above.
[0258] Conditions for Resolving 23d:
[0259] Chiral Technologies AD Chiralpak column (0.46 cm.times.25
cm).
[0260] Sample concentration: 17.55 mg/mL in 10:1 Hexanes:IPA
[0261] Flow rate: 1 mL/min.
[0262] Wavelength: 254
[0263] Injection volume: 10 .mu.L
[0264] Retention time first peak: 5.47 min.
[0265] Retention time second peak: 9.22 min.
[0266] Note: 30 .mu.L injection can also be separated (0.526
mg/injection).
[0267] Conditions for Resolving 25d:
[0268] Chiral Technologies AD Chiralpak column (2.0 cm.times.25
cm).
[0269] Sample concentration: 18.0 mg/mL in 15% IPA in hexanes
[0270] Flow rate: 6 mL/min.
[0271] Wavelength: 254
[0272] Injection volume: 500 .mu.L
[0273] Retention time first peak: 36.42 min. (optical rotation
=-36.9.degree. (0042, CHCl.sub.3)
[0274] Retention time second peak: 32.6 min. (optical
rotation=+35.7.degree. (0.0041, CHCl.sub.3)
[0275] Note: 2 injections produced 8 mg of each enantiomer.
EXAMPLE 2
Biological Assays
[0276] .sup.3H-Thymidine Incorporation Assay for an Inhibitory
Effect on the Proliferation of Human Umbilical Vein Endothelial
Cells (HUVEC)
[0277] HUVEC (Cascade Biologies, Inc.) were seeded at a density of
5,000 cells per well in 96-well plates with M-200 complete growth
medium (Cascade Biologies, Inc.) and incubated at 37.degree. C. for
three days. Cells were then serum-depleted by removing the growth
medium and replacing it with M-200+0.5% fetal bovine serum followed
by an overnight incubation at 37.degree. C. Basic fibroblast growth
factor (bFGF, Biosource International, Inc.) and compounds were
incubated with the cells for 22 h followed by the addition of 1
.mu.Ci of 3H-thymidine (NEN) to each well. After 2 hours, the cells
were harvested on a GF/B filter (Unifiler.TM.-96, GF/BTM, Packard)
using a 96-well cell harvester (Packard), and the filter was then
washed with water and ethanol. Scintillation liquid (50 .mu.L) was
added to each well and counted in TopCount Microplate Counter
NXT.TM.(Packard).
[0278] Cytotoxicity Assay Using HUVEC
[0279] HUVEC were seeded at a density of 5,000 cells per well in
96-well plates with M-200 complete growth medium and incubated at
37.degree. C. for three days. Cells were then washed twice with
M-200 medium and replaced with M-200+0.5% fetal bovine serum
followed by an overnight incubation at 37.degree. C. bFGF and
compounds were incubated with the cells for 24 h. Cytotoxicity was
evaluated with measuring ATP contents as a marker for cell
viability using ATP-Lite.TM.-M Luminescent ATP Detection Assay Kit
(Packard). ATP-Lite.TM.-M Luminescent ATP Detection Assay was
performed by the manufacturer's protocol, briefly, cell lysis
solution was mixed with the same volume of substrate solution
followed by 1 h incubation at room temperature, then the
luminescence was measured with TopCount Microplate Counter
NXT.TM.(Packard).
* * * * *
References