U.S. patent application number 11/960410 was filed with the patent office on 2008-09-04 for tetracyclic amino and carboxamido compounds and methods of use thereof.
Invention is credited to Prakash JAGTAP, Csaba Szabo.
Application Number | 20080214593 11/960410 |
Document ID | / |
Family ID | 36941478 |
Filed Date | 2008-09-04 |
United States Patent
Application |
20080214593 |
Kind Code |
A1 |
JAGTAP; Prakash ; et
al. |
September 4, 2008 |
TETRACYCLIC AMINO AND CARBOXAMIDO COMPOUNDS AND METHODS OF USE
THEREOF
Abstract
The present invention relates to Tetracyclic Amino Compounds and
Tetracyclic Carboxamido Compounds, compositions comprising an
effective amount of a Tetracyclic Amino Compound or a Tetracyclic
Carboxamido Compound and methods for treating or preventing an
inflammatory disease, a reperfusion injury, diabetes, a diabetic
complication, reoxygenation injury resulting from organ
transplantation, an ischemic condition, Parkinson's disease, renal
failure, a vascular disease, a cardiovascular disease, or cancer,
comprising administering to a subject in need thereof an effective
amount of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido
Compound.
Inventors: |
JAGTAP; Prakash; (Beverly,
MA) ; Szabo; Csaba; (Seattle, WA) |
Correspondence
Address: |
LAHIVE & COCKFIELD, LLP;FLOOR 30, SUITE 3000
ONE POST OFFICE SQUARE
BOSTON
MA
02109
US
|
Family ID: |
36941478 |
Appl. No.: |
11/960410 |
Filed: |
December 19, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11354707 |
Feb 15, 2006 |
7381722 |
|
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11960410 |
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60656636 |
Feb 25, 2005 |
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Current U.S.
Class: |
514/284 |
Current CPC
Class: |
A61P 37/06 20180101;
A61P 35/00 20180101; C07D 221/18 20130101; A61P 13/12 20180101;
A61P 19/02 20180101; A61P 11/00 20180101; A61K 31/473 20130101;
A61P 7/02 20180101; A61P 9/10 20180101; C07D 413/12 20130101; A61P
25/16 20180101; A61P 3/10 20180101; A61P 29/00 20180101; A61P 31/04
20180101; A61P 25/00 20180101; A61P 27/02 20180101; A61P 1/04
20180101; A61K 31/5377 20130101; A61K 31/496 20130101; C07D 401/12
20130101; A61P 1/02 20180101 |
Class at
Publication: |
514/284 |
International
Class: |
A61K 31/473 20060101
A61K031/473; A61P 35/00 20060101 A61P035/00; A61P 25/16 20060101
A61P025/16; A61P 3/10 20060101 A61P003/10 |
Claims
1-25. (canceled)
26. A method for treating cancer, comprising administering an
effective amount of a compound having the formula: ##STR00063## or
a pharmaceutically acceptable salt thereof wherein one of the
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 groups is
--C(O)NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and the remaining
groups are simultaneously --H; R.sup.5 and R.sup.6 are
independently --H, --C.sub.1-C.sub.6 alkyl, or -phenyl, wherein the
--C.sub.1-C.sub.6 alkyl, or -phenyl, is unsubstituted or
substituted with one or more of -halo, --OH or
--N(Z.sub.3)(Z.sub.4), where Z.sub.3 and Z.sub.4 are independently
--H or --C.sub.1-C.sub.5 alkyl, which is unsubstituted or
substituted with one or more of -halo, -hydroxy or --NH.sub.2; or
N, Z.sub.3 and Z.sub.4 are taken together to form an
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
or N, R.sup.5 and R.sup.6 are taken together to form a
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
and n is an integer ranging from 2 to 6 to a subject in need
thereof.
27. (canceled)
28. The method of claim 26, wherein the cancer is lung cancer,
breast cancer, colorectal cancer, prostate cancer, leukemia,
lymphoma, non-Hodgkin's lymphoma, skin cancer, brain cancer, a
cancer of the central nervous system, ovarian cancer, uterine
cancer, stomach cancer, pancreatic cancer, esophageal cancer,
kidney cancer, liver cancer, or a head and neck cancer.
29. (canceled)
30. The method of claim 26, further comprising the administration
of an effective amount of another anticancer agent.
31. (canceled)
32. The method of claim 30, wherein the other anticancer agent is
temozolomide, procarbazine, dacarbazine, interleukin-2, irinotecan,
or a combination thereof.
33-35. (canceled)
36. The method of claim 28, wherein the cancer is brain cancer or
melanoma.
37. The method of claim 36, wherein the brain cancer is metastatic
brain cancer or a glioma.
38. The method of claim 37, wherein the glioma is pilocytic
astrocytoma, astrocytoma, anaplastic astrocytoma or glioblastoma
multiforme.
39. (canceled)
40. A method for treating renal failure, comprising administering
an effective amount of a compound having the formula: ##STR00064##
or a pharmaceutically acceptable salt thereof wherein one of the
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 groups is
--C(O)NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and the remaining
groups are simultaneously --H; R.sup.5 and R.sup.6 are
independently --H, --C.sub.1-C.sub.6 alkyl, or -phenyl, wherein the
--C.sub.1-C.sub.6 alkyl, or -phenyl, is unsubstituted or
substituted with one or more of -halo, --OH or
--N(Z.sub.3)(Z.sub.4), where Z.sub.3 and Z.sub.4 are independently
--H or --C.sub.1-C.sub.5 alkyl, which is unsubstituted or
substituted with one or more of -halo, -hydroxy or --NH.sub.2; or
N, Z.sub.3 and Z.sub.4 are taken together to form an
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
or N, R.sup.5 and R.sup.6 are taken together to form a
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
and n is an integer ranging from 2 to 6 to a subject in need
thereof.
41. (canceled)
42. The method of claim 40, wherein the renal failure is chronic
renal failure or acute renal failure.
43. (canceled)
44. A method for treating a reperfusion injury, comprising
administering an effective amount of a compound having the formula:
##STR00065## or a pharmaceutically acceptable salt thereof wherein
one of the R.sup.1, R.sup.2, R.sup.3 and R.sup.4 groups is
--C(O)NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and the remaining
groups are simultaneously --H; R.sup.5 and R.sup.6 are
independently --H, --C.sub.1-C.sub.6 alkyl, or -phenyl, wherein the
--C.sub.1-C.sub.6 alkyl, or -phenyl, is unsubstituted or
substituted with one or more of -halo, --OH or
--N(Z.sub.3)(Z.sub.4), where Z.sub.3 and Z.sub.4 are independently
--H or --C.sub.1-C.sub.5 alkyl, which is unsubstituted or
substituted with one or more of -halo, -hydroxy or --NH.sub.2; or
N, Z.sub.3 and Z.sub.4 are taken together to form an
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
or N, R.sup.5 and R.sup.6 are taken together to form a
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
and n is an integer ranging from 2 to 6 to a subject in need
thereof.
45. (canceled)
46. The method of claim 44, wherein the reperfusion injury is
stroke or myocardial infarction.
47. (canceled)
48. A method for treating an inflammatory disease, comprising
administering an effective amount of a compound having the formula:
##STR00066## or a pharmaceutically acceptable salt thereof wherein
one of the R.sup.1, R.sup.2, R.sup.3 and R.sup.4 groups is
--C(O)NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and the remaining
groups are simultaneously --H; R.sup.5 and R.sup.6 are
independently --H, --C.sub.1-C.sub.6 alkyl, or -phenyl, wherein the
--C.sub.1-C.sub.6 alkyl, or -phenyl, is unsubstituted or
substituted with one or more of -halo, --OH or
--N(Z.sub.3)(Z.sub.4), where Z.sub.3 and Z.sub.4 are independently
--H or --C.sub.1-C.sub.5 alkyl, which is unsubstituted or
substituted with one or more of -halo, -hydroxy or --NH.sub.2; or
N, Z.sub.3 and Z.sub.4 are taken together to form an
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
or N, R.sup.5 and R.sup.6 are taken together to form a
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
and n is an integer ranging from 2 to 6 to a subject in need
thereof.
49. (canceled)
50. The method of claim 48, wherein the inflammatory disease is an
inflammatory disease of a joint, a chronic inflammatory disease of
the gum, an inflammatory bowel disease, an inflammatory lung
disease, an inflammatory disease of the central nervous system, an
inflammatory disease of the eye, gram-positive shock, gram negative
shock, hemorrhagic shock, anaphylactic shock, traumatic shock or
chemotherapeutic shock.
51. (canceled)
52. A method for treating or preventing diabetes, comprising
administering an effective amount of a compound having the formula:
##STR00067## or a pharmaceutically acceptable salt thereof wherein
one of the R.sup.1, R.sup.2, R.sup.3 and R.sup.4 groups is
--C(O)NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and the remaining
groups are simultaneously --H; R.sup.5 and R.sup.6 are
independently --H, C.sub.1-C.sub.6 alkyl, or -phenyl, wherein the
C.sub.1-C.sub.6 alkyl, or -phenyl, is unsubstituted or substituted
with one or more of -halo, --OH or --N(Z.sub.3)(Z.sub.4), where
Z.sub.3 and Z.sub.4 are independently --H or --C.sub.1-C.sub.5
alkyl, which is unsubstituted or substituted with one or more of
-halo, -hydroxy or --NH.sub.2; or N, Z.sub.3 and Z.sub.4 are taken
together to form an nitrogen-containing 3- to 7-membered monocyclic
heterocycle which is unsubstituted or substituted with one to three
of --C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted
C.sub.1-C.sub.5 alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl,
--N(R.sup.a).sub.2, --COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl),
--OC(O)--(C.sub.1-C.sub.5 alkyl), --C(O)NH.sub.2, or --NO.sub.2,
wherein each occurrence of R.sup.a is independently --H, -benzyl,
or --C.sub.1-C.sub.10 alkyl; or N, R.sup.5 and R.sup.6 are taken
together to form a nitrogen-containing 3- to 7-membered monocyclic
heterocycle which is unsubstituted or substituted with one to three
of --C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted
C.sub.1-C.sub.5 alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl,
--N(R.sup.a).sub.2, --COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl),
--OC(O)--(C.sub.1-C.sub.5 alkyl), --C(O)NH.sub.2, or --NO.sub.2,
wherein each occurrence of R.sup.a is independently --H, -benzyl,
or --C.sub.1-C.sub.10 alkyl; and n is an integer ranging from 2 to
6 to a subject in need thereof.
53. (canceled)
54. The method of claim 52, wherein the diabetes is type I diabetes
or type II diabetes.
55. (canceled)
56. A method for treating an ischemic condition, comprising
administering an effective amount of a compound having the formula:
##STR00068## or a pharmaceutically acceptable salt thereof wherein
one of the R.sup.1, R.sup.2, R.sup.3 and R.sup.4 groups is
--C(O)NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and the remaining
groups are simultaneously --H; R.sup.5 and R.sup.6 are
independently --C.sub.1-C.sub.6 alkyl, or -phenyl, wherein the
--C.sub.1-C.sub.6 alkyl, or -phenyl, is unsubstituted or
substituted with one or more of -halo, --OH or
--N(Z.sub.3)(Z.sub.4), where Z.sub.3 and Z.sub.4 are independently
--H or --C.sub.1-C.sub.5 alkyl, which is unsubstituted or
substituted with one or more of -halo, -hydroxy or --NH.sub.2; or
N, Z.sub.3 and Z.sub.4 are taken together to form an
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
or N, R.sup.5 and R.sup.6 are taken together to form a
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
and n is an integer ranging from 2 to 6 to a subject in need
thereof.
57. (canceled)
58. The method of claim 56, wherein the ischemic condition is
stable angina, unstable angina, myocardial ischemia, hepatic
ischemia, mesenteric ischemia, ischemic heart disease, intestinal
ischemia, limb ischemia, acute cardiac ischemia, stroke, or
cerebral ischemia.
59. (canceled)
60. A method for treating reoxygenation injury resulting from organ
transplantation, comprising administering an effective amount of a
compound having the formula: ##STR00069## or a pharmaceutically
acceptable salt thereof wherein one of the R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 groups is
--C(O)NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and the remaining
groups are simultaneously --H; R.sup.5 and R.sup.6 are
independently --H, --C.sub.1-C.sub.6 alkyl, or -phenyl, wherein the
--C.sub.1-C.sub.6 alkyl, or -phenyl, is unsubstituted or
substituted with one or more of -halo, --OH or
--N(Z.sub.3)(Z.sub.4), where Z.sub.3 and Z.sub.4 are independently
--H or --C.sub.1-C.sub.5 alkyl, which is unsubstituted or
substituted with one or more of -halo, -hydroxy or --NH.sub.2; or
N, Z.sub.3 and Z.sub.4 are taken together to form an
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
or N, R.sup.5 and R.sup.6 are taken together to form a
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
and n is an integer ranging from 2 to 6 to a subject in need
thereof.
61. (canceled)
62. A method for treating Parkinson's disease, comprising
administering an effective amount of a compound having the formula:
##STR00070## or a pharmaceutically acceptable salt thereof wherein
one of the R.sup.1, R.sup.2, R.sup.3 and R.sup.4 groups is
--C(O)NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and the remaining
groups are simultaneously --H; R.sup.5 and R.sup.6 are
independently --H, --C.sub.1-C.sub.6 alkyl, or -phenyl, wherein the
--C.sub.1-C.sub.6 alkyl, or -phenyl, is unsubstituted or
substituted with one or more of -halo, --OH or
--N(Z.sub.3)(Z.sub.4), where Z.sub.3 and Z.sub.4 are independently
--H or --C.sub.1-C.sub.5 alkyl, which is unsubstituted or
substituted with one or more of -halo, -hydroxy or --NH.sub.2; or
N, Z.sub.3 and Z.sub.4 are taken together to form an
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
or N, R.sup.5 and R.sup.6 are taken together to form a
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
and n is an integer ranging from 2 to 6 to a subject in need
thereof.
63. (canceled)
64. A method for treating a vascular disease, comprising
administering an effective amount of a compound having the formula:
##STR00071## or a pharmaceutically acceptable salt thereof wherein
one of the R.sup.1, R.sup.2, R.sup.3 and R.sup.4 groups is
--C(O)NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and the remaining
groups are simultaneously --H; R.sup.5 and R.sup.6 are
independently --H, --C.sub.1-C.sub.6 alkyl, or -phenyl, wherein the
--C.sub.1-C.sub.6 alkyl, or -phenyl, is unsubstituted or
substituted with one or more of -halo, --OH or
--N(Z.sub.3)(Z.sub.4), where Z.sub.3 and Z.sub.4 are independently
--H or --C.sub.1-C.sub.5 alkyl, which is unsubstituted or
substituted with one or more of -halo, -hydroxy or --NH.sub.2; or
N, Z.sub.3 and Z.sub.4 are taken together to form an
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
or N, R.sup.5 and R.sup.6 are taken together to form a
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
and n is an integer ranging from 2 to 6 to a subject in need
thereof.
65. (canceled)
66. The method of claim 64, wherein the vascular disease is
peripheral arterial occlusion, thromboangitis obliterans, Reynaud's
disease and phenomenon, acrocyanosis, erythromelalgia, venous
thrombosis, varicose veins, arteriovenous fistula, lymphedema or
lipedema.
67. (canceled)
68. A method for treating a diabetic complication, comprising
administering an effective amount of a compound having the formula:
##STR00072## or a pharmaceutically acceptable salt thereof wherein
one of the R.sup.1, R.sup.2, R.sup.3 and R.sup.4 groups is
--C(O)NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and the remaining
groups are simultaneously --H; R.sup.5 and R.sup.6 are
independently --H, --C.sub.1-C.sub.6 alkyl, or -phenyl, wherein the
--C.sub.1-C.sub.6 alkyl, or -phenyl, is unsubstituted or
substituted with one or more of -halo, --OH or
--N(Z.sub.3)(Z.sub.4), where Z.sub.3 and Z.sub.4 are independently
--H or --C.sub.1-C.sub.5 alkyl, which is unsubstituted or
substituted with one or more of -halo, -hydroxy or --NH.sub.2; or
N, Z.sub.3 and Z.sub.4 are taken together to form an
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
or N, R.sup.5 and R.sup.6 are taken together to form a
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
and n is an integer ranging from 2 to 6 to a subject in need
thereof.
69. (canceled)
70. A method for treating a cardiovascular disease, comprising
administering an effective amount of a compound having the formula:
##STR00073## or a pharmaceutically acceptable salt thereof wherein
one of the R.sup.1, R.sup.2, R.sup.3 and R.sup.4 groups is
--C(O)NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and the remaining
groups are simultaneously --H; R.sup.5 and R.sup.6 are
independently --H, --C.sub.1-C.sub.6 alkyl, or -phenyl, wherein the
--C.sub.1-C.sub.6 alkyl, or -phenyl, is unsubstituted or
substituted with one or more of -halo, --OH or
--N(Z.sub.3)(Z.sub.4), where Z.sub.3 and Z.sub.4 are independently
--H or --C.sub.1-C.sub.5 alkyl, which is unsubstituted or
substituted with one or more of -halo, -hydroxy or --NH.sub.2; or
N, Z.sub.3 and Z.sub.4 are taken together to form an
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
or N, R.sup.5 and R.sup.6 are taken together to form a
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
and n is an integer ranging from 2 to 6 to a subject in need
thereof.
71. (canceled)
72. The method of claim 70, wherein the cardiovascular disease is
chronic heart failure, atrial fibrillation, supraventricular
tachycardia, atrial flutter or paroxysmal atrial tachycardia.
73-82. (canceled)
83. The method of claim 26, wherein the cancer is colon cancer or
cancer of the central nervous system, further comprising
administering an effective amount of a DNA alkylating agent or a
topoisomerase inhibitor.
84. The method of claim 44, wherein the reperfusion injury is a
reperfusion injury resulting from cardiopulmonary bypass, resulting
from aortic aneurysm repair surgery, resulting from carotid
endarteretcomy surgery, or resulting from hemorrhagic shock.
85. The method of claim 84, wherein said carotid endarterectomy
surgery is angioplasty.
86. The method of claim 68, wherein the diabetic complication is
diabetic nephropathy, diabetic retinopathy, diabetic neuropathy or
diabetic cardiomyopathy.
87. The method of claim 26, wherein the cancer is a metastatic
malignant melanoma, a malignant melanoma, or glioblastoma
multiforme, further comprising administering an effective amount of
a DNA alkylating agent.
88. The method of claim 26, wherein the cancer is a adenocarcinoma,
lung cancer, fibrosarcoma, breast cancer, squamous cell carcinoma
or cervical cancer, further comprising administering an effective
amount of a radiation.
Description
[0001] This application is a divisional of U.S. application Ser.
No. 11/354,707, filed Feb. 15, 2006, the entirety of which is
incorporated herein by reference, which claims the benefit of U.S.
Provisional Application No. 60/656,636, filed Feb. 25, 2005, the
entirety of which is incorporated herein by reference.
1. FIELD OF THE INVENTION
[0002] The present invention relates to Tetracyclic Amino Compounds
and Tetracyclic Carboxamido Compounds, compositions comprising an
effective amount of a Tetracyclic Amino Compound or a Tetracyclic
Carboxamido Compound and methods for treating or preventing an
inflammatory disease, a reperfusion injury, diabetes, a diabetic
complication, reoxygenation injury resulting from organ
transplantation, an ischemic condition, Parkinson's disease, renal
failure, a vascular disease, a cardiovascular disease, or cancer,
comprising administering to a subject in need thereof an effective
amount of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido
Compound.
2. BACKGROUND OF THE INVENTION
[0003] Inflammatory diseases, such as arthritis, colitis, and
autoimmune diabetes, typically manifest themselves as disorders
distinct from those associated with reperfusion injuries, e.g.,
stroke and heart attack, and can clinically manifest themselves as
different entities. However, there can be common underlying
mechanisms between these two types of disorders. In particular,
inflammatory disease and reperfusion injury can induce
proinflammatory cytokine and chemokine synthesis which can, in
turn, result in production of cytotoxic free radicals such as
nitric oxide and superoxide. NO and superoxide can react to form
peroxynitrite (ONOO.sup.-) (Szabo et al., Shock 6:79-88, 1996).
[0004] The ONOO.sup.- induced cell necrosis observed in
inflammatory disease and in reperfusion injury involves the
activation of the nuclear enzyme poly (ADP-ribose) synthetase
(PARS). Activation of PARS is thought to be an important step in
the cell-mediated death observed in inflammation and reperfusion
injury (Szabo et al., Trends Pharmacol. Sci. 19:287-98, 1998).
[0005] A number of PARS inhibitors have been described in the art.
See, e.g., Banasik et al., J. Biol. Chem., 267:1569-75, 1992, and
Banasik et al., Mol. Cell. Biochem., 138:185-97, 1994; WO 00/39104;
WO 00/39070; WO 99/59975; WO 99/59973; WO 99/11649; WO 99/11645; WO
99/11644; WO 99/11628; WO 99/11623; WO 99/11311; WO 00/42040; Zhang
et al., Biochem. Biophys. Res. Commun., 278:590-98, 2000; White et
al., J. Med. Chem., 43:4084-4097, 2000; Griffin et al., J. Med.
Chem., 41:5247-5256, 1998; Shinkwin et al., Bioorg. Med. Chem.,
7:297-308, 1999; and Soriano et al., Nature Medicine, 7:108-113,
2001. Adverse effects associated with administration of PARS
inhibitors have been discussed in Milan et al., Science,
223:589-591, 1984.
[0006] Isoquinoline compounds have been previously discussed in the
art. For example, cytotoxic non-camptothecin topoisomerase I
inhibitors are reported in Cushman et al., J. Med. Chem.,
43:3688-3698, 2300 and Cushman et al., J. Med. Chem. 42:446-57,
1999; indeno[1,2-c]isoquinolines are reported as antineoplastic
agents in Cushman et al., WO 00/21537; and as neoplasm inhibitors
in Hrbata et al., WO 93/05023.
[0007] Syntheses of isoquinoline compounds have been reported. For
example, see Wawzonek et al., Org. Prep. Proc. Int., 14:163-8,
1982; Wawzonek et al., Can. J. Chem., 59:2833, 1981; Andoi et al.,
Bull. Chem. Soc. Japan, 47:1014-17, 1974; Dusemund et al., Arch.
Pharm (Weinheim, Ger.), 3 17:381-2, 1984; and Lal et al., Indian J.
Chem., Sect. B, 38B:33-39, 1999.
[0008] There remains, however, a need in the art for compounds
useful for treating or preventing an inflammatory disease, a
reperfusion injury, diabetes, a diabetic complication,
reoxygenation injury resulting from organ transplantation, an
ischemic preventing condition, Parkinson's disease, renal failure,
a vascular disease, a cardiovascular disease, or cancer.
[0009] Citation of any reference in Section 2 of this application
is not an admission that the reference is prior art.
3. SUMMARY OF THE INVENTION
[0010] In one aspect the invention provides a compound of Formula
(I)
##STR00001##
and pharmaceutically acceptable salts thereof wherein
[0011] one of the R.sup.1, R.sup.2, R.sup.3 and R.sup.4 groups is
--NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and the remaining groups
are simultaneously --H;
[0012] R.sup.5 and R.sup.6 are independently --H, --C.sub.1-C.sub.6
alkyl, -phenyl, or benzyl, wherein the --C.sub.1-C.sub.6 alkyl,
-phenyl, or benzyl, is unsubstituted or substituted with one or
more of -halo, --OH or --N(Z.sub.3)(Z.sub.4), where Z.sub.3 and
Z.sub.4 are independently --H or --C.sub.1-C.sub.5 alkyl, which is
unsubstituted or substituted with one or more of -halo, -hydroxy or
--NH.sub.2; or N, Z.sub.3 and Z.sub.4 are taken together to form an
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl;
or N, R.sup.5 and R.sup.6 are taken together to form a
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, phenyl, benzyl, hydroxy-substituted
C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, halo-substituted phenyl, hydroxy, --O--C.sub.1-C.sub.5
alkyl, --(O--C.sub.1-C.sub.5-alkyl)-substituted phenyl,
cyano-substituted phenyl, --N(R.sup.a).sub.2, --(C.sub.1-C.sub.5
alkylene)-N(R.sup.a).sub.2, --COOH, --(C.sub.1-C.sub.5
alkylene)-COOH, --(C.sub.1-C.sub.5 alkylene)-C(O)O--C.sub.1-C.sub.5
alkyl, --(C.sub.1-C.sub.5-alkylene)-C(O)NH--C.sub.1-C.sub.5 alkyl,
--C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5 alkyl),
--C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of R.sup.a
is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl; and
[0013] n is an integer ranging from 2 to 6.
[0014] In another aspect the invention includes a compound of
Formula (II)
##STR00002##
and pharmaceutically acceptable salts thereof wherein
[0015] one of the R.sup.1, R.sup.2, R.sup.3 and R.sup.4 groups is
--C(O)NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and the remaining
groups are simultaneously --H;
[0016] R.sup.5 and R.sup.6 are independently --H, --C.sub.1-C.sub.6
alkyl, -phenyl, or benzyl, wherein the --C.sub.1-C.sub.6 alkyl,
-phenyl, or benzyl, is unsubstituted or substituted with one or
more of -halo, --OH or --N(Z.sub.3)(Z.sub.4), where Z.sub.3 and
Z.sub.4 are independently --H or --C.sub.1-C.sub.5 alkyl, which is
unsubstituted or substituted with one or more of -halo, -hydroxy or
--NH.sub.2; or N, Z.sub.3 and Z.sub.4 are taken together to form an
nitrogen-containing 3- to 7-membered monocyclic heterocycle which
is unsubstituted or substituted with one to three of
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or N, R.sup.5 and R.sup.6 are taken
together to form a nitrogen-containing 3- to 7-membered monocyclic
heterocycle which is unsubstituted or substituted with one to three
of --C.sub.1-C.sub.5 alkyl, phenyl, benzyl, hydroxy-substituted
C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, halo-substituted phenyl, hydroxy, --O--C.sub.1-C.sub.5
alkyl, --(O--C.sub.1-C.sub.5-alkyl)-substituted phenyl,
cyano-substituted phenyl, --N(R.sup.a).sub.2, --(C.sub.1-C.sub.5
alkylene)-N(R.sup.a).sub.2, --COOH, --(C.sub.1-C.sub.5
alkylene)-COOH, --(C.sub.1-C.sub.5 alkylene)-C(O)O--C.sub.1-C.sub.5
alkyl, --(C.sub.1-C.sub.5-alkylene)-C(O)NH--C.sub.1-C.sub.5 alkyl,
--C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5 alkyl),
--C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of R.sup.a
is independently --H, -benzyl, or --C.sub.1-C.sub.10 alkyl; and
[0017] n is an integer ranging from 2 to 6.
[0018] A Compound of Formula (I) or a pharmaceutically acceptable
salt thereof (a "Tetracyclic Amino Compound") and a compound of
Formula (II) or a pharmaceutically acceptable salt thereof (a
"Tetracyclic Carboxamido Compound") are useful for treating or
preventing an inflammatory disease, a reperfusion injury, diabetes,
a diabetic complication, reoxygenation injury resulting from organ
transplantation, an ischemic condition, Parkinson's disease, renal
failure, a vascular disease, a cardiovascular disease, or cancer
(each being a "Condition").
[0019] Also provided by the invention are methods for treating or
preventing a Condition, comprising administering to a subject in
need of such treatment or prevention an effective amount of a
Tetracyclic Amino Compound.
[0020] The invention further provides compositions comprising and
an effective amount of a Tetracyclic Amino Compound and a
physiologically acceptable carrier or vehicle.
[0021] Also provided by the invention are methods for treating or
preventing a Condition, comprising administering to a subject in
need of such treatment or prevention an effective amount of a
Tetracyclic Carboxamido Compound.
[0022] The invention provides compositions comprising and an
effective amount of a Tetracyclic Carboxamido Compound and a
physiologically acceptable carrier or vehicle.
[0023] The details of the invention are set forth in the
accompanying description below.
[0024] Although any methods and materials similar or equivalent to
those described herein can be used in the practice or testing of
the present invention, illustrative methods and materials are now
described. Other features, objects, and advantages of the invention
will be apparent from the description and from the claims. All
patents and publications cited in this specification are
incorporated by reference.
4. DETAILED DESCRIPTION OF THE INVENTION
4.1 Definitions and Abbreviations
[0025] The following definitions are used in connection with the
Tetracyclic Amino Compounds and the Tetracyclic Carboxamido
Compounds:
[0026] The term "--C.sub.1-C.sub.5 alkyl" as used herein, refers to
a straight chain or branched non-cyclic hydrocarbon having from 1
to 5 carbon atoms, wherein one of the hydrocarbon's hydrogen atoms
has been replaced by a single bond. Representative straight chain
--C.sub.1-C.sub.5 alkyls include -methyl, -ethyl, -n-propyl,
-n-butyl and -n-pentyl. Representative branched --C.sub.1-C.sub.5
alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl,
-isopentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl,
3-methylbutyl, 1,1-dimethylpropyl and 1,2-dimethylpropyl.
[0027] The term "--C.sub.1-C.sub.6 alkyl" as used herein, refers to
a straight chain or branched non-cyclic hydrocarbon having from 1
to 6 carbon atoms, wherein one of the hydrocarbon's hydrogen atoms
has been replaced by a single bond. Representative straight chain
--C.sub.1-C.sub.6 alkyls include -methyl, -ethyl, -n-propyl,
-n-butyl, -n-pentyl and -n-hexyl. Representative branched
--C.sub.1-C.sub.6 alkyls include -isopropyl, -sec-butyl, -isobutyl,
-tert-butyl, -isopentyl, -neopentyl, -1-methylbutyl, -isohexyl,
-neohexyl, -2-methylbutyl, -3-methylbutyl, -1,1-dimethylpropyl and
-1,2-dimethylpropyl.
[0028] The term "--C.sub.1-C.sub.10 alkyl" as used herein, refers
to a straight chain or branched non-cyclic hydrocarbon having from
1 to 10 carbon atoms, wherein one of the hydrocarbon's hydrogen
atoms has been replaced by a single bond. Representative
--C.sub.1-C.sub.10 alkyls include, methyl, ethyl, propyl, butyl,
pentyl, hexyl, heptyl, octyl, -nonyl, decyl, isopropyl, isobutyl,
sec-butyl and tert-butyl, isopentyl, neopentyl, isohexyl,
isoheptyl, isooctyl, isononyl and isodecyl.
[0029] The term "--C.sub.1-C.sub.5 alkylene-" as used herein,
refers to a straight chain or branched acylic hydrocarbon having
from 1-5 carbon atoms, wherein two of the hydrocarbon's hydrogen
atoms has been replaced by a single bond. Representative
--C.sub.1-C.sub.5 alkylene- groups include methylene, ethylene,
propylene, butylene, and pentylene. Other --C.sub.1-C.sub.5
alkylene- groups include --CH(CH.sub.3)--,
--CH.sub.2CH(CH.sub.3)--, --CH.sub.2CH.sub.2CH(CH.sub.3)--,
--CH.sub.2CH(CH.sub.3)CH.sub.2--, --CH(CH.sub.3)CH(CH.sub.3)--,
--CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3)--,
--CH.sub.2CH.sub.2CH(CH.sub.3)CH.sub.2--,
--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2-- and
--CH(CH.sub.3)CH.sub.2CH(CH.sub.3)--.
[0030] A "nitrogen containing 3- to 7-membered monocyclic
heterocycle" refers to a monocyclic 3- to 7-membered aromatic or
non-aromatic monocyclic cycloalkyl group in which one of the
cycloalkyl group's ring carbon atoms has been replaced with a
nitrogen atom and 0-4 of the cycloalkyl group's remaining ring
carbon atoms may be independently replaced with a N, O or S atom.
The nitrogen containing 3- to 7-membered monocyclic heterocycles
can be attached via a nitrogen, sulfur, or carbon atom.
Representative examples of nitrogen-containing-3- to 7-membered
monocyclic heterocycles include, but are not limited to,
piperidinyl, piperazinyl, pyrrolyl, oxazinyl, thiazinyl, diazinyl,
triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl,
isoxazolyl, pyridinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,
pyrimidinyl, and morpholinyl. In one embodiment, a nitrogen
containing 3- to 7-membered monocyclic heterocycle is substituted
with up to three groups, independently chosen from:
--C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted C.sub.1-C.sub.5
alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl, --N(R.sup.a).sub.2,
--COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl), --OC(O)--(C.sub.1-C.sub.5
alkyl), --C(O)NH.sub.2, or --NO.sub.2, wherein each occurrence of
R.sup.a is independently --H, -benzyl, or --C.sub.1-C.sub.10
alkyl.
[0031] "Halo" is --F, --Cl, --Br or --I.
[0032] A "subject" is a mammal, e.g., a human, mouse, rat, guinea
pig, dog, cat, horse, cow, pig, or non-human primate, such as a
monkey, chimpanzee, baboon or rhesus. In one embodiment, the
subject is a human.
[0033] Representative "pharmaceutically acceptable salts" include,
e.g., water-soluble and water-insoluble salts, such as the acetate,
amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate,
benzonate, bicarbonate, bisulfate, bitartrate, borate, butyrate,
calcium edetate, camphorsulfonate, camsylate, carbonate, citrate,
clavulariate, dihydrochloride, edetate, edisylate, estolate,
esylate, fumarate, fumarate, gluceptate, gluconate, glutamate,
glycollylarsanilate, hexafluorophosphate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide, isothionate, lactate, lactobionate, laurate, malate,
maleate, mandelate, mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, N-methylglucamine
ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate,
pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate),
pantothenate, phosphate/diphosphate, picrate, polygalacturonate,
propionate, p-toluenesulfonate, salicylate, stearate, subacetate,
succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate,
teoclate, tosylate, triethiodide, and valerate salts. A hydrate is
another example of a pharmaceutically acceptable salt.
[0034] In one embodiment, the pharmaceutically acceptable salt is a
mesylate salt.
[0035] In another embodiment, the pharmaceutically acceptable salt
is a camphorsulfonate salt.
[0036] An "effective amount" when used in connection with a
Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound is
an amount that is effective for treating or preventing a
Condition.
[0037] An "effective amount" when used in connection with another
anticancer agent is an amount that is effective for treating or
preventing cancer alone or in combination with a Tetracyclic Amino
Compound or a Tetracyclic Carboxamido Compound. "In combination
with" includes administration within the same composition and
within separate compositions. In the latter instance, the
anticancer agent is administered during a time when the Tetracyclic
Amino Compound or the Tetracyclic Carboxamido Compound exerts its
prophylactic or therapeutic effect, or vice versa.
4.2 The Tetracyclic Amino Compounds of Formula (I)
[0038] The present invention provides Tetracyclic Amino Compounds
according to Formula (I), below:
##STR00003##
and pharmaceutically acceptable salts thereof, wherein:
[0039] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above
for the compounds of formula (I).
[0040] In one embodiment, R.sup.1 is
--NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and R.sup.2, R.sup.3 and
R.sup.4 are each hydrogen.
[0041] In another embodiment, R.sup.2 is
--NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and R.sup.1, R.sup.3 and
R.sup.4 are each hydrogen.
[0042] In another embodiment, R.sup.3 is
--NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and R.sup.1, R.sup.2 and
R.sup.4 are each hydrogen.
[0043] In still another embodiment, R.sup.4 is
--NH(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and R.sup.1, R.sup.2 and
R.sup.3 are each hydrogen.
[0044] In another embodiment, n is 2.
[0045] In still another embodiment, n is 3.
[0046] In yet another embodiment, n is 4.
[0047] In a further embodiment, n is 5.
[0048] In another embodiment, n is 6.
[0049] In another embodiment N, R.sup.5 and R.sup.6 are taken
together to form a nitrogen-containing 3- to 7-membered monocyclic
heterocycle which is unsubstituted or substituted with one to three
of --C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted
C.sub.1-C.sub.5 alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl,
--N(R.sup.a).sub.2, --COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl),
--OC(O)--(C.sub.1-C.sub.5 alkyl), --C(O)NH.sub.2, or --NO.sub.2,
wherein each occurrence of R.sup.a is independently --H, -benzyl,
or --C.sub.1-C.sub.10 alkyl.
[0050] In various embodiments, --N(R.sup.5)(R.sup.6) is:
##STR00004## ##STR00005##
[0051] Illustrative examples of the Tetracyclic Amino Compounds of
Formula (I) include the compounds of Formula (Ia) as set forth
below:
TABLE-US-00001 (Ia) ##STR00006## Compound n --N(R.sup.5)(R.sup.6)
1a 2 --N(CH.sub.3).sub.2 1b 3 --N(CH.sub.3).sub.2 1c 4
--N(CH.sub.3).sub.2 1d 5 --N(CH.sub.3).sub.2 1e 6
--N(CH.sub.3).sub.2 2a 2 ##STR00007## 2b 3 ##STR00008## 2c 4
##STR00009## 2d 5 ##STR00010## 2e 6 ##STR00011##
[0052] and pharmaceutically acceptable salts thereof.
[0053] Other illustrative examples of the Tetracyclic Amino
Compounds of Formula (I) include the compounds of Formula (Ib) as
set forth below:
TABLE-US-00002 (Ib) ##STR00012## Compound n --N(R.sup.5)(R.sup.6)
3a 2 --N(CH.sub.3).sub.2 3c 3 --N(CH.sub.3).sub.2 3c 4
--N(CH.sub.3).sub.2 3d 5 --N(CH.sub.3).sub.2 3e 6
--N(CH.sub.3).sub.2 4a 2 ##STR00013## 4b 3 ##STR00014## 4c 4
##STR00015## 4d 5 ##STR00016## 4e 6 ##STR00017##
and pharmaceutically acceptable salts thereof.
[0054] Other illustrative examples of the Tetracyclic Amino
Compounds of Formula (I) include the compounds of Formula (Ic) as
set forth below:
TABLE-US-00003 (Ic) ##STR00018## Compound n --N(R.sup.5)(R.sup.6)
5a 2 --N(CH.sub.3).sub.2 5b 3 --N(CH.sub.3).sub.2 5c 4
--N(CH.sub.3).sub.2 5d 5 --N(CH.sub.3).sub.2 5e 6
--N(CH.sub.3).sub.2 6a 2 ##STR00019## 6b 3 ##STR00020## 6c 4
##STR00021## 6d 5 ##STR00022## 6e 6 ##STR00023##
and pharmaceutically acceptable salts thereof.
[0055] Other illustrative examples of the Tetracyclic Amino
Compounds of Formula (I) include the compounds of Formula (Id) as
set forth below:
TABLE-US-00004 (Id) ##STR00024## Compound n --N(R.sup.5)(R.sup.6)
7a 2 --N(CH.sub.3).sub.2 7b 3 --N(CH.sub.3).sub.2 7c 4
--N(CH.sub.3).sub.2 7d 5 --N(CH.sub.3).sub.2 7e 6
--N(CH.sub.3).sub.2 8a 2 ##STR00025## 8b 3 ##STR00026## 8c 4
##STR00027## 8d 5 ##STR00028## 8e 6 ##STR00029##
and pharmaceutically acceptable salts thereof.
4.3 The Tetracyclic Carboxamido Compounds of Formula (II)
[0056] The present invention provides Tetracyclic Carboxamido
Compounds according to Formula (II), below:
##STR00030##
and pharmaceutically acceptable salts thereof, wherein:
[0057] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above
for the compounds of formula (II).
[0058] In one embodiment, R.sup.1 is
--C(O)NH--(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and R.sup.2,
R.sup.3 and R.sup.4 are each hydrogen.
[0059] In another embodiment, R.sup.2 is
--C(O)NH--(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and R.sup.1,
R.sup.3 and R.sup.4 are each hydrogen.
[0060] In another embodiment, R.sup.3 is
--C(O)NH--(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and R.sup.1,
R.sup.2 and R.sup.4 are each hydrogen.
[0061] In still another embodiment, R.sup.4 is
--C(O)NH--(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6) and R.sup.1,
R.sup.2 and R.sup.3 are each hydrogen.
[0062] In another embodiment, n is 2.
[0063] In still another embodiment, n is 3.
[0064] In yet another embodiment, n is 4.
[0065] In a further embodiment, n is 5.
[0066] In another embodiment N, R.sup.5 and R.sup.6 are taken
together to form a nitrogen-containing 3- to 7-membered monocyclic
heterocycle which is unsubstituted or substituted with one to three
of --C.sub.1-C.sub.5 alkyl, -halo, -halo-substituted
C.sub.1-C.sub.5 alkyl, hydroxy, --O--C.sub.1-C.sub.5 alkyl,
--N(R.sup.a).sub.2, --COOH, --C(O)O--(C.sub.1-C.sub.5 alkyl),
--OC(O)--(C.sub.1-C.sub.5 alkyl), --C(O)NH.sub.2, or --NO.sub.2,
wherein each occurrence of R.sup.a is independently --H, -benzyl,
or --C.sub.1-C.sub.10 alkyl.
[0067] In various embodiments, --N(R.sup.5)(R.sup.6) is:
##STR00031## ##STR00032##
[0068] Illustrative examples of the Tetracyclic Carboxamido
Compounds of Formula (II) include the compounds of Formula (IIa) as
set forth below:
TABLE-US-00005 (IIa) ##STR00033## Compound n --N(R.sup.5)(R.sup.6)
9a 2 --N(CH.sub.3).sub.2 9b 3 --N(CH.sub.3).sub.2 9c 4
--N(CH.sub.3).sub.2 9d 5 --N(CH.sub.3).sub.2 10a 2 ##STR00034## 10b
3 ##STR00035## 10c 4 ##STR00036## 10d 5 ##STR00037##
[0069] and pharmaceutically acceptable salts thereof.
[0070] Other illustrative examples of the Tetracyclic Carboxamido
Compounds of Formula (II) include the compounds of Formula (IIb) as
set forth below:
TABLE-US-00006 (IIb) ##STR00038## Compound n --N(R.sup.5)(R.sup.6)
11a 2 --N(CH.sub.3).sub.2 11b 3 --N(CH.sub.3).sub.2 11c 4
--N(CH.sub.3).sub.2 11d 5 --N(CH.sub.3).sub.2 12a 2 ##STR00039##
12b 3 ##STR00040## 12c 4 ##STR00041## 12d 5 ##STR00042##
and pharmaceutically acceptable salts thereof.
[0071] Other illustrative examples of the Tetracyclic Carboxamido
Compounds of Formula (II) include the compounds of Formula (IIc) as
set forth below:
TABLE-US-00007 (IIc) ##STR00043## Compound n --N(R.sup.5)(R.sup.6)
13a 2 --N(CH.sub.3).sub.2 13b 3 --N(CH.sub.3).sub.2 13c 4
--N(CH.sub.3).sub.2 13d 5 --N(CH.sub.3).sub.2 14a 2 ##STR00044##
14b 3 ##STR00045## 14c 4 ##STR00046## 14d 5 ##STR00047##
and pharmaceutically acceptable salts thereof.
[0072] Other illustrative examples of the Tetracyclic Carboxamido
Compounds of Formula (II) include the compounds of Formula (IId) as
set forth below:
TABLE-US-00008 (IId) ##STR00048## Compound n --N(R.sup.5)(R.sup.6)
15a 2 --N(CH.sub.3).sub.2 15b 3 --N(CH.sub.3).sub.2 15c 4
--N(CH.sub.3).sub.2 15d 5 --N(CH.sub.3).sub.2 16a 2 ##STR00049##
16b 3 ##STR00050## 16c 4 ##STR00051## 16d 5 ##STR00052##
and pharmaceutically acceptable salts thereof.
4.4 Methods for Making the Tetracyclic Amino Compounds or the
Tetracyclic Carboxamido Compounds
[0073] Methods useful for making the Tetracyclic Amino Compounds
and the Tetracyclic Carboxamido Compounds are set forth in the
Examples below and generalized in Schemes 1-4.
##STR00053##
wherein each X is independently --Cl or --Br, and n, R.sup.5 and
R.sup.6 are defined above for the Compounds of Formula (I).
[0074] Homophthalic anhydride 1 can be coupled with a nitrobenzene
compound of formula 2 in the presence of a base, for example, an
amine base, to provide a tetracyclic nitro intermediate of formula
3. The nitro group of 3 can be reduced using, for example,
catalytic hydrogenation with a platinum or palladium catalyst, to
provide an amino compound of formula 4. A compound of formula 4 can
then be reacted with a stoichiometric excess of an acid halide
compound of formula 5 to provide an amido compound of formula 6.
The chlorine or bromine atom of 6 can then be displaced by an amine
of formula NH(R.sup.5)(R.sup.6) to provide an amino compound of
formula 7. Finally, the amide moiety of a compound of formula 7 can
be reduced using lithium aluminum hydride to provide the
Tetracyclic Amino Compounds of Formula (I).
##STR00054##
wherein R is methyl or ethyl, and n, R.sup.5 and R.sup.6 are
defined above for the Compounds of Formula (II).
[0075] Homophthalic anhydride 1 can be coupled with a phenylester
compound of formula 2 in the presence of a base, for example, an
amine base, to provide a tetracyclic nitro intermediate of formula
3. The ester group of 3 can be hydrolyzed under basic or acidic
conditions to provide an carboxylic acid compound of formula 4. A
compound of formula 3 or formula 4 can then be coupled with a
diaminoalkyl compound of formula 5 (which is commercially
available, or can be prepared by reacting dihaloalkyl compounds
with various amines using methods well known to one of skill in the
art of organic synthesis) to provide the Tetracyclic Carboxamido
Compounds of Formula (II).
##STR00055##
wherein n, R.sup.5 and R.sup.6 are defined as above for compounds
of formula (IIc).
[0076] Compounds of Formula (IIc) can be made according to the
general procedure of Scheme 3. Bromocarboxylic acid 1 can be
reacted with methanol and sulfuric acid under reflux to give the
bromo ester 2. The bromo ester 2 can be converted to the cyano
ester 3 using, for example, Pd(OAc).sub.2 and
K.sub.4[Fe(CN).sub.6]. Treatment of compound 3 with
N-bromosuccinamide and benzoyl peroxide provides bromobenzyl
compound 4. Reaction of compound 4 with homophthalic anhydride in
acetonitrile provides the fused ring structure of compound 5.
Hydrolysis of the ester of compound 5 followed by addition of a
coupling agent and the desired amine provides the Tetracyclic
Carboxamido Compounds of Formula (IIc).
##STR00056##
wherein n, R.sup.5 and R.sup.6 are defined as above for compounds
of formula (IId).
[0077] Compounds of Formula (IId) can be made according to the
general procedure of Scheme 4. Bromocarboxylic acid 1 can be
reacted with methanol and sulfuric acid under reflux to give the
bromo ester 2. The bromo ester 2 can be converted to the cyano
ester 3 using, for example, Pd(OAc).sub.2 and
K.sub.4[Fe(CN).sub.6]. Treatment of compound 3 with
N-bromosuccinamide and benzoyl peroxide provides bromobenzyl
compound 4. Reaction of compound 4 with homophthalic anhydride in
acetonitrile provides the fused ring structure of compound 5.
Hydrolysis of the ester of compound 5 followed by addition of a
coupling agent and the desired amine provides the Tetracyclic
Carboxamido Compounds of Formula (IId).
4.5 Uses of the Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds
[0078] In accordance with the invention, the Tetracyclic Amino
Compounds or the Tetracyclic Carboxamido Compounds are administered
to a subject in need of treatment or prevention of a Condition.
4.5.1 Treatment or Prevention of an Inflammatory Disease
[0079] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can be used to treat an inflammatory disease.
Inflammatory diseases can arise where there is an inflammation of
the body tissue. These include local inflammatory responses and
systemic inflammation. Examples of inflammatory diseases treatable
or preventable using the Tetracyclic Amino Compounds or the
Tetracyclic Carboxamido Compounds include, but are not limited to,
organ transplant rejection; chronic inflammatory diseases of the
joints, including arthritis, rheumatoid arthritis, osteoarthritis
and bone diseases associated with increased bone resorption;
inflammatory bowel diseases such as ileitis, ulcerative colitis,
Barrett's syndrome, and Crohn's disease; inflammatory lung diseases
such as asthma, adult respiratory distress syndrome, and chronic
obstructive airway disease; inflammatory diseases of the eye
including corneal dystrophy, trachoma, onchocerciasis, uveitis,
sympathetic ophthalmitis and endophthalmitis; chronic inflammatory
diseases of the gum, including gingivitis and periodontitis;
tuberculosis; leprosy; inflammatory diseases of the kidney
including uremic complications, glomerulonephritis and nephrosis;
inflammatory diseases of the skin including sclerodermatitis,
psoriasis and eczema; inflammatory diseases of the central nervous
system, including chronic demyelinating diseases of the nervous
system, multiple sclerosis, AIDS-related neurodegeneration and
Alzheimer's disease, infectious meningitis, encephalomyelitis,
Huntington's disease, amyotrophic lateral sclerosis and viral or
autoimmune encephalitis; as well as various other diseases that can
have significant inflammatory components, including preeclampsia,
chronic liver failure, and brain and spinal cord trauma. The
inflammatory disease can also be a systemic inflammation of the
body, exemplified by gram-positive or gram negative shock,
hemorrhagic or anaphylactic shock, or shock induced by cancer
chemotherapy in response to pro-inflammatory cytokines, e.g., shock
associated with pro-inflammatory cytokines. Such shock can be
induced, e.g., by a chemotherapeutic agent that is administered as
a treatment for cancer.
[0080] In one embodiment, the inflammatory disease is the
inflammatory disease is an inflammatory disease of a joint, a
chronic inflammatory disease of the gum, an inflammatory bowel
disease, an inflammatory lung disease, an inflammatory disease of
the central nervous system, an inflammatory disease of the eye,
gram-positive shock, gram negative shock, hemorrhagic shock,
anaphylactic shock, traumatic shock or chemotherapeutic shock.
4.5.2 Treatment or Prevention of a Reperfusion Injury
[0081] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can be used to treat a reperfusion injury.
Reperfusion refers to the process whereby blood flow in the blood
vessels is resumed following ischemia, such as occurs following
constriction or obstruction of the vessel. Reperfusion injury can
result following a naturally occurring episode, such as a
myocardial infarction, stroke, or during a surgical procedure where
blood flow in vessels is intentionally or unintentionally blocked.
Examples of reperfusion injuries treatable or preventable using the
Tetracyclic Amino Compounds or the Tetracyclic Carboxamido
Compounds include, but are not limited to, intestinal reperfusion
injury, myocardial reperfusion injury, and reperfusion injury
resulting from cardiopulmonary bypass surgery, aortic aneurysm
repair surgery, carotid endarterectomy surgery, or hemorrhagic
shock.
[0082] In one embodiment, the reperfusion injury results from
cardiopulmonary bypass surgery, aortic aneurysm repair surgery,
carotid endarterectomy surgery or hemorrhagic shock.
4.5.3 Treatment or Prevention of Reoxygenation Injury Resulting
from Organ Transplantation
[0083] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can be used to treat or prevent reoxygenation
injury resulting from organ transplantation. Examples of
reoxygenation injuries treatable or preventable using the
Tetracyclic Amino Compounds or the Tetracyclic Carboxamido
Compounds include, but are not limited to, transplantation of the
following organs: heart, lung, liver, kidney, pancreas, intestine
and cornea.
[0084] In one embodiment, reoxygenation injury resulting from organ
transplantation occurs during the organ transplantation.
4.5.4 Treatment or Prevention of an Ischemic Condition
[0085] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can be used to treat or prevent an ischemic
condition. Examples of ischemic conditions treatable or preventable
using the Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds include, but are not limited to, stable
angina, unstable angina, myocardial ischemia, hepatic ischemia,
mesenteric artery ischemia, ischemic heart disease, intestinal
ischemia, critical limb ischemia, chronic critical limb ischemia,
cerebral ischemia, acute cardiac ischemia, and an ischemic disease
of the central nervous system, such as stroke or cerebral
ischemia.
[0086] In one embodiment, the ischemic condition is myocardial
ischemia, stable angina, unstable angina, stroke, ischemic heart
disease or cerebral ischemia.
4.5.5 Treatment or Prevention of Renal Failure
[0087] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can be used to treat or prevent renal
failure.
[0088] In one embodiment, the renal failure is chronic renal
failure.
[0089] In another embodiment, the renal failure is acute renal
failure.
4.5.6 Treatment or Prevention of a Vascular Disease
[0090] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can be used to treat or prevent a vascular
disease other than a cardiovascular disease. Examples of vascular
diseases treatable or preventable using the Tetracyclic Amino
Compounds or the Tetracyclic Carboxamido Compounds include, but are
not limited to, peripheral arterial occlusion, thromboangitis
obliterans, Reynaud's disease and phenomenon, acrocyanosis,
erythromelalgia, venous thrombosis, varicose veins, arteriovenous
fistula, lymphedema, and lipedema.
4.5.7 Treatment or Prevention of a Cardiovascular Disease
[0091] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can be used to treat or prevent a
cardiovascular disease. Examples of cardiovascular diseases
treatable or preventable using the Tetracyclic Amino Compounds or
the Tetracyclic Carboxamido Compounds include, but are not limited
to, chronic heart failure, atherosclerosis, congestive heart
failure, hypercholesterolemia, circulatory shock, cardiomyopathy,
cardiac transplant, myocardial infarction, and a cardiac
arrhythmia, such as atrial fibrillation, supraventricular
tachycardia, atrial flutter, and paroxysmal atrial tachycardia.
[0092] In one embodiment, the cardiovascular disease is chronic
heart failure.
[0093] In another embodiment, the cardiovascular disease is a
cardiac arrhythmia.
[0094] In still another embodiment, the cardiac arrhythmia is
atrial fibrillation, supraventricular tachycardia, atrial flutter
or paroxysmal atrial tachycardia.
4.5.8 Treatment or Prevention of Diabetes or a Diabetic
Complication
[0095] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can be used to treat or prevent diabetes
mellitus or its complications. Examples of diabetes mellitus that
are treatable or preventable using the Tetracyclic Amino Compounds
or the Tetracyclic Carboxamido Compounds include, but are not
limited to, Type I diabetes (Insulin Dependent Diabetes Mellitus),
Type II diabetes (Non-Insulin Dependent Diabetes Mellitus),
gestational diabetes, autoimmune diabetes, insulinopathies,
diabetes due to pancreatic disease, diabetes associated with other
endocrine diseases (such as Cushing's Syndrome, acromegaly,
pheochromocytoma, glucagonoma, primary aldosteronism or
somatostatinoma), Type A insulin resistance syndrome, Type B
insulin resistance syndrome, lipatrophic diabetes, and diabetes
induced by .beta.-cell toxins.
[0096] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can also be used to treat or prevent a
complication of diabetes mellitus. Examples of complications of
diabetes mellitus that are treatable or preventable using the
Tetracyclic Amino Compounds or the Tetracyclic Carboxamido
Compounds include, but are not limited to, diabetic cataract,
glaucoma, retinopathy, nephropathy, (such as microaluminuria and
progressive diabetic nephropathy), polyneuropathy, gangrene of the
feet, immune-complex vasculitis, systemic lupus erythematosus
(SLE), atherosclerotic coronary arterial disease, peripheral
arterial disease, nonketotic hyperglycemic-hyperosmolar coma,
mononeuropathies, autonomic neuropathy, foot ulcers, joint
problems, and a skin or mucous membrane complication (such as an
infection, a shin spot, a candidal infection or necrobiosis
lipoidica diabeticorumobesity), hyperlipidemia, hypertension,
syndrome of insulin resistance, coronary artery disease,
retinopathy, diabetic neuropathy, polyneuropathy, mononeuropathies,
autonomic neuropathy, a foot ulcer, a joint problem, a fungal
infection, cardiomyopathy, and a bacterial infection.
4.5.9 Treatment or Prevention of Parkinson's Disease
[0097] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can be used to treat or prevent Parkinson's
disease.
4.5.10 Treatment or Prevention of Cancer
[0098] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can be used to treat or prevent cancer.
[0099] The invention provides methods for treating or preventing
cancer, comprising administering to a subject in need of such
treatment or prevention: (i) an effective amount of a Tetracyclic
Amino Compound; and (ii) an effective amount of another anticancer
agent.
[0100] The invention further provides methods for treating or
preventing cancer, comprising administering to a subject in need of
such treatment or prevention: (i) an effective amount of a
Tetracyclic Carboxamido Compound; and (ii) an effective amount of
the other anticancer agent.
[0101] Examples of cancers treatable or preventable using the
Tetracyclic Amino Compounds or the Tetracyclic Carboxamido
Compounds include, but are not limited to, the cancers disclosed
below in Table 1 and metastases thereof.
TABLE-US-00009 TABLE 1 Solid tumors, including but not limited to:
fibrosarcoma myxosarcoma liposarcoma chondrosarcoma osteogenic
sarcoma chordoma angiosarcoma endotheliosarcoma lymphangiosarcoma
lymphangioendotheliosarcoma synovioma mesothelioma Ewing's tumor
leiomyosarcoma rhabdomyosarcoma colon cancer colorectal cancer
kidney cancer pancreatic cancer bone cancer breast cancer ovarian
cancer prostate cancer esophageal cancer stomach cancer oral cancer
nasal cancer throat cancer squamous cell carcinoma basal cell
carcinoma adenocarcinoma sweat gland carcinoma sebaceous gland
carcinoma papillary carcinoma papillary adenocarcinomas
cystadenocarcinoma medullary carcinoma bronchogenic carcinoma renal
cell carcinoma hepatoma bile duct carcinoma choriocarcinoma
seminoma embryonal carcinoma Wilms' tumor cervical cancer uterine
cancer testicular cancer small cell lung carcinoma bladder
carcinoma lung cancer epithelial carcinoma skin cancer melanoma
metastatic melanoma neuroblastoma retinoblastoma blood-borne
cancers, including but not limited to: acute lymphoblastic leukemia
("ALL") acute lymphoblastic B-cell leukemia acute lymphoblastic
T-cell leukemia acute myeloblastic leukemia ("AML") acute
promyelocytic leukemia ("APL") acute monoblastic leukemia acute
erythroleukemic leukemia acute megakaryoblastic leukemia acute
myelomonocytic leukemia acute nonlymphocyctic leukemia acute
undifferentiated leukemia chronic myelocytic leukemia ("CML")
chronic lymphocytic leukemia ("CLL") hairy cell leukemia multiple
myeloma acute and chronic leukemias: lymphoblastic myelogenous
lymphocytic myelocytic leukemias Lymphomas: Hodgkin's disease
non-Hodgkin's Lymphoma Multiple myeloma Waldenstrom's
macroglobulinemia Heavy chain disease Polycythemia vera Central
nervous system lymphomas CNS and Brain cancers: glioma pilocytic
astrocytoma astrocytoma anaplastic astrocytoma glioblastoma
multiforme medulloblastoma craniopharyngioma ependymoma pinealoma
hemangioblastoma acoustic neuroma oligodendroglioma meningioma
vestibular schwannoma adenoma metastatic brain tumor meningioma
spinal tumor medulloblastoma
[0102] In one embodiment the cancer is lung cancer, breast cancer,
colorectal cancer, prostate cancer, a leukemia, a lymphoma,
non-Hodgkin's lymphoma, skin cancer, a brain cancer, a cancer of
the central nervous system, ovarian cancer, uterine cancer, stomach
cancer, pancreatic cancer, esophageal cancer, kidney cancer, liver
cancer, or a head and neck cancer.
[0103] In another embodiment the cancer is metastatic cancer.
[0104] In still another embodiment, the subject in need of
treatment has previously undergone or is presently undergoing
treatment for cancer. The treatment includes, but is not limited
to, prior chemotherapy, radiation therapy, surgery or
immunotherapy, such as administration of cancer vaccines.
[0105] The Tetracyclic Amino Compound or the Tetracyclic
Carboxamido Compounds are also useful for the treatment or
prevention of a cancer caused by a virus. Such viruses include
human papilloma virus, which can lead to cervical cancer (see,
e.g., Hernandez-Avila et al., Archives of Medical Research (1997)
28:265-271); Epstein-Barr virus (EBV), which can lead to lymphoma
(see, e.g., Herrmann et al., J Pathol (2003) 199(2):140-5);
hepatitis B or C virus, which can lead to liver carcinoma (see,
e.g., El-Serag, J Clin Gastroenterol (2002) 35(5 Suppl 2):S72-8);
human T cell leukemia virus (HTLV)-I, which can lead to T-cell
leukemia (see e.g., Mortreux et al., Leukemia (2003) 17(1):26-38);
human herpesvirus-8 infection, which can lead to Kaposi's sarcoma
(see, e.g., Kadow et al., Curr Opin Investig Drugs (2002) 3(11):
1574-9); and Human Immune deficiency Virus (HIV) infection, which
can lead to cancer as a consequence of immunodeficiency (see, e.g.,
Dal Maso et al., Lancet Oncol (2003) 4(2):110-9).
4.5.10.1 Prophylactic Methods for Cancer
[0106] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can also be administered to prevent the
progression of a cancer, including but not limited to the cancers
listed in Table 1. Such prophylactic use includes that in which
non-neoplastic cell growth consisting of hyperplasia, metaplasia,
or most particularly, dysplasia has occurred.
[0107] Alternatively or in addition to the presence of abnormal
cell growth characterized as hyperplasia, metaplasia, or dysplasia,
the presence of one or more characteristics of a transformed
phenotype, or of a malignant phenotype, displayed in vivo or
displayed in vitro by a cell sample from a subject, can indicate
the desirability of prophylactic or therapeutic administration of a
Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound.
Such characteristics of a transformed phenotype include morphology
changes, looser substratum attachment, loss of contact inhibition,
loss of anchorage dependence, protease release, increased sugar
transport, decreased serum requirement, expression of fetal
antigens, disappearance of the 250,000 dalton cell surface protein,
etc. (see also id., at pp. 84-90 for characteristics associated
with a transformed or malignant phenotype).
[0108] In a specific embodiment, leukoplakia, a benign-appearing
hyperplastic or dysplastic lesion of the epithelium, or Bowen's
disease, a carcinoma in situ, are treatable or preventable
according to the present methods.
[0109] In another embodiment, fibrocystic disease (cystic
hyperplasia, mammary dysplasia, particularly adenosis (benign
epithelial hyperplasia)) are treatable or preventable according to
the present methods.
[0110] In other embodiments, a subject that has one or more of the
following predisposing factors for malignancy can be treated by
administration of an effective amount of a Tetracyclic Amino
Compound or a Tetracyclic Carboxamido Compound: a chromosomal
translocation associated with a malignancy (e.g., the Philadelphia
chromosome for chronic myelogenous leukemia; t(14; 18) for
follicular lymphoma); familial polyposis or Gardner's syndrome;
benign monoclonal gammopathy; a first degree kinship with persons
having a cancer or precancerous disease showing a Mendelian
(genetic) inheritance pattern (e.g., familial polyposis of the
colon, Gardner's syndrome, hereditary exostosis, polyendocrine
adenomatosis, medullary thyroid carcinoma with amyloid production
and pheochromocytoma, Peutz-Jeghers syndrome, neurofibromatosis of
Von Recklinghausen, retinoblastoma, carotid body tumor, cutaneous
melanocarcinoma, intraocular melanocarcinoma, xeroderma
pigmentosum, ataxia telangiectasia, Chediak-Higashi syndrome,
albinism, Fanconi's aplastic anemia, and Bloom's syndrome; and
exposure to carcinogens (e.g., smoking, second-hand smoke exposure,
and inhalation of or contacting with certain chemicals).
4.5.10.2 Combination Chemotherapy for the Treatment of Cancer
[0111] In one aspect, the present methods for treating or
preventing cancer can further comprise the administration of
another anticancer agent.
[0112] In one embodiment, the present invention provides methods
for treating or preventing cancer, comprising the administration of
an effective amount of the following to a subject in need thereof:
(i) a Tetracyclic Amino Compound and (ii) another anticancer
agent.
[0113] In another embodiment, the present invention provides
methods for treating or preventing cancer in a subject, the method
comprising the administration of an effective amount of the
following to a subject in need thereof: (i) a Tetracyclic
Carboxamido Compound and (ii) another anticancer agent.
[0114] The (i) Tetracyclic Amino Compound or Tetracyclic
Carboxamide Compound and (ii) other anticancer agent can be
administered concurrently. In this embodiment the (i) Tetracyclic
Amino Compound or Tetracyclic Carboxamide Compound and (ii) other
anticancer agent can be administered within the same composition,
or can be administered from different compositions, via the same or
different routes of administration.
[0115] In another embodiment, the Tetracyclic Amino Compound or
Tetracyclic Carboxamide Compound is administered during a time when
the other anticancer agent exerts its prophylactic or therapeutic
effect, or vice versa.
[0116] In one embodiment, the Tetracyclic Amino Compound or other
anticancer agent are administered in doses commonly employed when
such agents are used as monotherapy for the treatment of
cancer.
[0117] In another embodiment, the Tetracyclic Carboxamido Compound
or other anticancer agent are administered in doses commonly
employed when such agents are used as monotherapy for the treatment
of cancer.
[0118] In one embodiment, the Tetracyclic Amino Compound or other
anticancer agent are administered in doses that are lower than the
doses commonly employed when such agents are used as monotherapy
for the treatment of cancer.
[0119] In another embodiment, the Tetracyclic Carboxamido Compound
or other anticancer agent are administered in doses that are lower
than the doses commonly employed when such agents are used as
monotherapy for the treatment of cancer.
[0120] In one embodiment, the Tetracyclic Amino Compound and other
anticancer agent act synergistically and are administered in doses
that are lower than the doses commonly employed when such agents
are used as monotherapy for the treatment of cancer.
[0121] In another embodiment the Tetracyclic Carboxamido Compound
and other anticancer agent act synergistically and are administered
in doses that are lower than the doses commonly employed when such
agents are used as monotherapy for the treatment of cancer.
[0122] The dosage of the Tetracyclic Amino Compound or other
anticancer agent administered as well as the dosing schedule can
depend on various parameters, including, but not limited to, the
cancer being treated, the subject's general health, and the
administering physician's discretion.
[0123] The dosage of the Tetracyclic Carboxamido Compound or other
anticancer agent administered as well as the dosing schedule can
depend on various parameters, including, but not limited to, the
cancer being treated, the subject's general health, and the
administering physician's discretion.
[0124] A Tetracyclic Amino Compound or a Tetracyclic Carboxamido
Compound can be administered prior to (e.g., 5 minutes, 15 minutes,
30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12
hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3
weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before),
concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes,
30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12
hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3
weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the
administration of the other anticancer agent, to a subject in need
thereof. In various embodiments a (i) Tetracyclic Amino Compound or
a Tetracyclic Carboxamido Compound and (ii) the other anticancer
agent are administered 1 minute apart, 10 minutes apart, 30 minutes
apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours
apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours
to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours
apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours
to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours
apart, no more than 24 hours apart or no more than 48 hours apart.
In one embodiment, a (i) Tetracyclic Amino Compound or a
Tetracyclic Carboxamido Compound and (ii) the other anticancer
agent are administered within 3 hours. In another embodiment, a (i)
Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound
and (ii) the other anticancer agent are administered at 1 minute to
24 hours apart.
[0125] In one embodiment, an effective amount of a Tetracyclic
Amino Compound and an effective amount of another anticancer agent
are present in the same composition. In one embodiment, this
composition is useful for oral administration. In another
embodiment, this composition is useful for intravenous
administration.
[0126] In one embodiment, an effective amount of a Tetracyclic
Carboxamido Compound and an effective amount of another anticancer
agent are present in the same composition. In one embodiment, this
composition is useful for oral administration. In another
embodiment, this composition is useful for intravenous
administration.
[0127] Cancers that can be treated or prevented by administering a
(i) Tetracyclic Amino Compound or a Tetracyclic Carboxamido
Compound and (ii) the other anticancer agent include, but are not
limited to, the list of cancers set forth above in Table 1.
[0128] In one embodiment, the cancer is brain cancer.
[0129] In specific embodiments, the brain cancer is pilocytic
astrocytoma, astrocytoma, anaplastic astrocytoma, glioblastoma
multiforme or a metastatic brain tumor.
[0130] In one embodiment, the cancer is melanoma.
[0131] In a specific embodiment, the melanoma is metastatic
melanoma.
[0132] The (i) Tetracyclic Amino Compound or Tetracyclic
Carboxamido Compound and (ii) other anticancer agent, can act
additively or synergistically. A synergistic combination of a (i)
Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound
and (ii) the other anticancer agent, might allow the use of lower
dosages of one or both of these agents and/or less frequent
administration of the agents to a subject with cancer. The ability
to utilize lower dosages of one or both of the (i) Tetracyclic
Amino Compound or Tetracyclic Carboxamido Compound and (ii) other
anticancer agent and/or to administer the agents less frequently
can reduce any toxicity associated with the administration of the
agents to a subject without reducing the efficacy of the agents in
the treatment of cancer. In addition, a synergistic effect might
result in the improved efficacy of these agents in the treatment of
cancer and/or the reduction of any adverse or unwanted side effects
associated with the use of either agent alone.
[0133] In one embodiment, the (i) Tetracyclic Amino Compound or
Tetracyclic Carboxamido Compound and (ii) one or more other
anticancer agents act synergistically when administered in doses
typically employed when such agents are used as monotherapy for the
treatment of cancer. In another embodiment, the (i) Tetracyclic
Amino Compound or Tetracyclic Carboxamido Compound and (ii) one or
more other anticancer agents act synergistically when administered
in doses that are lower than doses typically employed when such
agents are used as monotherapy for the treatment of cancer.
[0134] In one embodiment, the administration of an effective amount
of (i) a Tetracyclic Amino Compound or Tetracyclic Carboxamido
Compound and (ii) an effective amount of another anticancer agent
inhibits the resistance of a cancer to the other anticancer agent.
In one embodiment, the cancer is a tumor.
[0135] Suitable other anticancer agents useful in the methods and
compositions of the present invention include, but are not limited
to temozolomide, a topoisomerase I inhibitor, procarbazine,
dacarbazine, gemcitabine, capecitabine, methotrexate, taxol,
taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine,
cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin,
mitomycin, dacarbazine, procarbizine, etoposide, teniposide,
camptothecins, bleomycin, doxorubicin, idarubicin, daunorubicin,
dactinomycin, plicamycin, mitoxantrone, L-asparaginase,
doxorubicin, epirubicin, 5-fluorouracil, taxanes such as docetaxel
and paclitaxel, leucovorin, levamisole, irinotecan, estramustine,
etoposide, nitrogen mustards, BCNU, nitrosoureas such as carmustine
and lomustine, vinca alkaloids such as vinblastine, vincristine and
vinorelbine, platinum complexes such as cisplatin, carboplatin and
oxaliplatin, imatinib mesylate, hexamethylmelamine, topotecan,
tyrosine kinase inhibitors, tyrphostins herbimycin A, genistein,
erbstatin, and lavendustin A.
[0136] In one embodiment, the other anticancer agent is, but is not
limited to, a drug listed in Table 2.
TABLE-US-00010 TABLE 2 Alkylating agents Nitrogen mustards:
Cyclophosphamide Ifosfamide Trofosfamide Chlorambucil Nitrosoureas:
Carmustine (BCNU) Lomustine (CCNU) Alkylsulphonates: Busulfan
Treosulfan Triazenes: Dacarbazine Procarbazine Temozolomide
Platinum containing complexes: Cisplatin Carboplatin Aroplatin
Oxaliplatin Plant Alkaloids Vinca alkaloids: Vincristine
Vinblastine Vindesine Vinorelbine Taxoids: Paclitaxel Docetaxel DNA
Topoisomerase Inhibitors Epipodophyllins: Etoposide Teniposide
Topotecan 9-aminocamptothecin Camptothecin Crisnatol Mitomycins:
Mitomycin C Anti-metabolites Anti-folates: DHFR inhibitors:
Methotrexate Trimetrexate IMP dehydrogenase Inhibitors:
Mycophenolic acid Tiazofurin Ribavirin EICAR Ribonuclotide
reductase Hydroxyurea Inhibitors: Deferoxamine Pyrimidine analogs:
Uracil analogs: 5-Fluorouracil Fluoxuridine Doxifluridine
Ralitrexed Cytosine analogs: Cytarabine (ara C) Cytosine
arabinoside Fludarabine Gemcitabine Capecitabine Purine analogs:
Mercaptopurine Thioguanine DNA Antimetabolites: 3-HP
2'-deoxy-5-fluorouridine 5-HP alpha-TGDR aphidicolin glycinate
ara-C 5-aza-2'-deoxycytidine beta-TGDR cyclocytidine guanazole
inosine glycodialdehyde macebecin II Pyrazoloimidazole Hormonal
therapies: Receptor antagonists: Anti-estrogen: Tamoxifen
Raloxifene Megestrol LHRH agonists: Goscrclin Leuprolide acetate
Anti-androgens: Flutamide Bicalutamide Retinoids/Deltoids
Cis-retinoic acid Vitamin A derivative: All-trans retinoic acid
(ATRA-IV) Vitamin D3 analogs: EB 1089 CB 1093 KH 1060 Photodynamic
therapies: Vertoporfin (BPD-MA) Phthalocyanine Photosensitizer Pc4
Demethoxy-hypocrellin A (2BA-2-DMHA) Cytokines: Interferon-.alpha.
Interferon-.beta. Interferon-.gamma. Tumor necrosis factor
Interleukin-2 Angiogenesis Inhibitors: Angiostatin (plasminogen
fragment) antiangiogenic antithrombin III Angiozyme ABT-627 Bay
12-9566 Benefin Bevacizumab BMS-275291 cartilage-derived inhibitor
(CDI) CAI CD59 complement fragment CEP-7055 Col 3 Combretastatin
A-4 Endostatin (collagen XVIII fragment) Fibronectin fragment
Gro-beta Halofuginone Heparinases Heparin hexasaccharide fragment
HMV833 Human chorionic gonadotropin (hCG) IM-862 Interferon
alpha/beta/gamma Interferon inducible protein (IP- 10)
Interleukin-12 Kringle 5 (plasminogen fragment) Marimastat
Metalloproteinase inhibitors (TIMPs) 2-Methoxyestradiol MMI 270
(COS 27023A) MoAb IMC-1C11 Neovastat NM-3 Panzem PI-88 Placental
ribonuclease inhibitor Plasminogen activator inhibitor Platelet
factor-4 (PF4) Prinomastat Prolactin 16 kD fragment
Proliferin-related protein (PRP) PTK 787/ZK 222594 Retinoids
Solimastat Squalamine SS 3304 SU 5416 SU6668 SU11248
Tetrahydrocortisol-S Tetrathiomolybdate Thalidomide
Thrombospondin-1 (TSP-1) TNP-470 Transforming growth factor-beta
(TGF-.beta.) Vasculostatin Vasostatin (calreticulin fragment)
ZD6126 ZD 6474 farnesyl transferase inhibitors (FTI)
Bisphosphonates Antimitotic agents: Allocolchicine Halichondrin B
Colchicine colchicine derivative dolstatin 10 Maytansine Rhizoxin
Thiocolchicine trityl cysteine Others: Isoprenylation inhibitors:
Dopaminergic neurotoxins: 1-methyl-4-phenylpyridinium ion Cell
cycle inhibitors: Staurosporine Actinomycins: Actinomycin D
Dactinomycin Bleomycins: Bleomycin A2 Bleomycin B2 Peplomycin
Anthracyclines: Daunorubicin Doxorubicin (adriamycin) Idarubicin
Epirubicin Pirarubicin Zorubicin Mitoxantrone MDR inhibitors:
Verapamil Ca.sup.2+ATPase inhibitors: Thapsigargin
[0137] Other additional anticancer agents that can be used in the
compositions and methods of the present invention include, but are
not limited to: acivicin; aclarubicin; acodazole hydrochloride;
acronine; adozelesin; aldesleukin; altretamine; ambomycin;
ametantrone acetate; aminoglutethimide; amsacrine; anastrozole;
anthramycin; asparaginase; asperlin; azacitidine; azetepa;
azotomycin; batimastat; benzodepa; bicalutamide; bisantrene
hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;
brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;
caracemide; carbetimer; carboplatin; carmustine; carubicin
hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;
cisplatin; cladribine; crisnatol mesylate; cyclophosphamide;
cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride;
decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;
diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;
droloxifene; droloxifene citrate; dromostanolone propionate;
duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin;
enloplatin; enpromate; epipropidine; epirubicin hydrochloride;
erbulozole; esorubicin hydrochloride; estramustine; estramustine
phosphate sodium; etanidazole; etoposide; etoposide phosphate;
etoprine; fadrozole hydrochloride; fazarabine; fenretinide;
floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine;
fosquidone; fostriecin sodium; gemcitabine hydrochloride;
hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine;
interleukin-2 (including recombinant interleukin-2, or rIL2),
interferon alfa-2.alpha.; interferon alfa-2.beta.; interferon
alfa-n1; interferon alfa-n3; interferon beta-I.alpha.; interferon
gamma-I.beta.; iproplatin; irinotecan hydrochloride; lanreotide
acetate; letrozole; leuprolide acetate; liarozole hydrochloride;
lometrexol sodium; lomustine; losoxantrone hydrochloride;
masoprocol; maytansine; mechlorethamine hydrochloride; megestrol
acetate; melengestrol acetate; melphalan; menogaril;
mercaptopurine; methotrexate; methotrexate sodium; metoprine;
meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;
mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazole; nogalamycin;
ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;
pentamustine; peplomycin sulfate; perfosfamide; pipobroman;
piposulfan; piroxantrone hydrochloride; plicamycin; plomestane;
porfimer sodium; porfiromycin; prednimustine; procarbazine
hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin;
riboprine; rogletimide; safingol; safingol hydrochloride;
semustine; simtrazene; sparfosate sodium; sparsomycin;
spirogermanium hydrochloride; spiromustine; spiroplatin;
streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan
sodium; tegafur; teloxantrone hydrochloride; temoporfin;
teniposide; teroxirone; testolactone; thiamiprine; thioguanine;
thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone
acetate; triciribine phosphate; trimetrexate; trimetrexate
glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard;
uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine
sulfate; vindesine; vindesine sulfate; vinepidine sulfate;
vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;
vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;
zinostatin; zorubicin hydrochloride.
[0138] Further anticancer drugs that can be used in the methods and
compositions of the invention include, but are not limited to:
20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;
aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin;
ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta Lactam
Derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; canarypox IL-2;
carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN
700; cartilage derived inhibitor; carzelesin; casein kinase
inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-acytidine; dihydrotaxol; dioxamycin; diphenyl
spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;
droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;
edelfosine; edrecolomab; eflornithine; elemene; emitefur;
epirubicin; epristeride; estramustine analogue; estrogen agonists;
estrogen antagonists; etanidazole; etoposide phosphate; exemestane;
fadrozole; fazarabine; fenretinide; filgrastim; finasteride;
flavopiridol; flezelastine; fluasterone; fludarabine;
fluorodaunorunicin hydrochloride; forfenimex; formestane;
fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;
galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;
glutathione inhibitors; hepsulfam; heregulin; hexamethylene
bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;
idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod;
immunostimulant peptides; insulin-like growth factor-1 receptor
inhibitor; interferon agonists; interferons; interleukins;
iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;
isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia
inhibiting factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum complexes; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;
lysofylline; lytic peptides; maitansine; mannostatin A; marimastat;
masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase
inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone; miltefosine;
mirimostim; mismatched double stranded RNA; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
monoclonal antibody, human chorionic gonadotrophin; monophosphoryl
lipid A+myobacterium cell wall sk; mopidamol; multiple drug
resistance gene inhibitor; multiple tumor suppressor 1-based
therapy; mustard anticancer agents; mycaperoxide B; mycobacterial
cell wall extract; myriaporone; N-acetyldinaline; N-substituted
benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;
naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;
neutral endopeptidase; nilutamide; nisamycin; nitric oxide
modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine;
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;
oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;
paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic
acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;
pentrozole; perflubron; perfosfamide; perillyl alcohol;
phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;
pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;
placetin B; plasminogen activator inhibitor; platinum complex;
platinum complexes; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylene conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rogletimide; rohitukine; romurtide;
roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;
sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence
derived inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; signal transduction modulators; single chain antigen
binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium
phenylacetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stem cell inhibitor; stem-cell division
inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista;
suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;
tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;
temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;
thaliblastine; thiocoraline; thrombopoietin; thrombopoietin
mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan;
thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;
titanocene bichloride; topsentin; toremifene; totipotent stem cell
factor; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; vector system,
erythrocyte gene therapy; velaresol; veramine; verdins;
verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[0139] In one another embodiment, the other anticancer agent is
interferon-.alpha..
[0140] In another embodiment, the other anticancer agent is
interleukin-2.
[0141] In one embodiment, the other anticancer agent is an
alkylating agent, such as a nitrogen mustard, a nitrosourea, an
alkylsulfonate, a triazene, or a platinum-containing agent.
[0142] In one embodiment, the other anticancer agent is a triazene
alkylating agent.
[0143] In a specific embodiment, the other anticancer agent is
temozolomide.
[0144] Temozolomide can be administered to a subject at dosages
ranging from about 60 mg/m.sup.2 (of a subject's body surface area)
to about 250 mg/m.sup.2 and from about 100 mg/m.sup.2 to about 200
mg/m.sup.2. In specific embodiments, the dosages of temozolomide
are about 10 mg/m.sup.2, about 1 mg/m.sup.2, about 5 mg/m.sup.2,
about 10 mg/m.sup.2, about 20 mg/m.sup.2, about 30 mg/m.sup.2,
about 40 mg/m.sup.2, about 50 mg/m.sup.2, about 60 mg/m.sup.2,
about 70 mg/m.sup.2, about 80 mg/m.sup.2, about 90 mg/m.sup.2,
about 100 mg/m.sup.2, about 110 mg/m.sup.2, about 120 mg/m.sup.2,
about 130 mg/m.sup.2, about 140 mg/m.sup.2, about 150 mg/m.sup.2,
about 160 mg/m.sup.2, about 170 mg/m.sup.2, about 180 mg/m.sup.2,
about 190 mg/m.sup.2, about 200 mg/m.sup.2, about 210 mg/m.sup.2,
about 220 mg/m.sup.2, about 230 mg/m.sup.2, about 240 mg/m.sup.2,
or about 250 mg/m.sup.2.
[0145] In a particular embodiment, temozolomide is administered
orally.
[0146] In one embodiment, temozolomide is administered orally to a
subject at a dose ranging from about 150 mg/m.sup.2 to about 200
mg/m.sup.2.
[0147] In another embodiment, temozolomide is administered orally
to a subject once per day for five consecutive days at a dose
ranging from about 150 mg/m.sup.2 to about 200 mg/m.sup.2.
[0148] In a specific embodiment, temozolomide is administered
orally to a subject once per day for five consecutive days at a
dose ranging from about 150 mg/m.sup.2 to about 200 mg/m.sup.2 on
days 1-5, then again orally once per day for five consecutive days
on days 28-32 at a dose ranging from about 150 mg/m.sup.2 to about
200 mg/m.sup.2, then again orally once per day for five consecutive
days on days 55-59 at a dose ranging from about 150 mg/m.sup.2 to
about 200 mg/m.sup.2.
[0149] In a specific embodiment, the other anticancer agent is
procarbazine.
[0150] Procarbazine can be administered to a subject at dosages
ranging from about 50 mg/m.sup.2 (of a subject's body surface area)
to about 100 mg/m.sup.2 and from about 60 mg/m.sup.2 to about 100
mg/m.sup.2. In specific embodiments, the dosages of procarbazine
are about 10 mg/m.sup.2, about 1 mg/m.sup.2, about 5 mg/m.sup.2,
about 10 mg/m.sup.2, about 20 mg/m.sup.2, about 30 mg/m.sup.2,
about 40 mg/m.sup.2, about 50 mg/m.sup.2, about 60 mg/m.sup.2,
about 70 mg/m.sup.2, about 80 mg/m.sup.2, about 90 mg/m.sup.2,
about 100 mg/m.sup.2, about 110 mg/m.sup.2, about 120 mg/m.sup.2,
about 130 mg/m.sup.2, about 140 mg/m.sup.2, about 150 mg/m.sup.2,
about 160 mg/m.sup.2, about 170 mg/m.sup.2, about 180 mg/m.sup.2,
about 190 mg/m.sup.2, about 200 mg/m.sup.2, about 210 mg/m.sup.2,
about 220 mg/m.sup.2, about 230 mg/m.sup.2, about 240 mg/m.sup.2,
about 250 mg/m.sup.2, about 260 mg/m.sup.2, about 270 mg/m.sup.2,
about 280 mg/m.sup.2, about 290 mg/m.sup.2, about 300 mg/m.sup.2,
about 310 mg/m.sup.2, about 320 mg/m.sup.2, about 330 mg/m.sup.2,
about 340 mg/m.sup.2, about 350 mg/m.sup.2, about 360 mg/m.sup.2,
about 370 mg/m.sup.2, about 380 mg/m.sup.2, about 390 mg/m.sup.2,
about 400 mg/m.sup.2, about 410 mg/m.sup.2, about 420 mg/m.sup.2,
about 430 mg/m.sup.2, about 440 mg/m.sup.2, about 450 mg/m.sup.2,
about 460 mg/m.sup.2, about 470 mg/m.sup.2, about 480 mg/m.sup.2,
about 490 mg/m.sup.2, or about 500 mg/m.sup.2.
[0151] In a particular embodiment, procarbazine is administered
intravenously.
[0152] In one embodiment, procarbazine is administered
intravenously to a subject at a dose ranging from about 50
mg/m.sup.2 to about 100 mg/m.sup.2.
[0153] In another embodiment, procarbazine is administered
intravenously to a subject once per day for five consecutive days
at a dose ranging from about 50 mg/m.sup.2 to about 100
mg/m.sup.2.
[0154] In a specific embodiment, procarbazine is administered
intravenously to a subject once per day for five consecutive days
at a dose ranging from about 50 mg/m.sup.2 to about 100 mg/m.sup.2
on days 1-5, then again intravenously once per day for five
consecutive days on days 28-32 at a dose ranging from about 50
mg/m.sup.2 to about 100 mg/m.sup.2, then again intravenously once
per day for five consecutive days on days 55-59 at a dose ranging
from about 50 mg/m.sup.2 to about 100 mg/m.sup.2.
[0155] In another embodiment, procarbazine is administered once
intravenously to a subject at a dose ranging from about 50
mg/m.sup.2 to about 100 mg/m.sup.2.
[0156] In a specific embodiment, the other anticancer agent is
dacarbazine.
[0157] Dacarbazine can be administered to a subject at dosages
ranging from about 60 mg/m.sup.2 (of a subject's body surface area)
to about 250 mg/m.sup.2 and from about 150 mg/m.sup.2 to about 250
mg/m.sup.2. In specific embodiments, the dosages of dacarbazine are
about 10 mg/m.sup.2, about 1 mg/m.sup.2, about 5 mg/m.sup.2, about
10 mg/m.sup.2, about 20 mg/m.sup.2, about 30 mg/m.sup.2, about 40
mg/m.sup.2, about 50 mg/m.sup.2, about 60 mg/m.sup.2, about 70
mg/m.sup.2, about 80 mg/m.sup.2, about 90 mg/m.sup.2, about 100
mg/m.sup.2, about 110 mg/m.sup.2, about 120 mg/m.sup.2, about 130
mg/m.sup.2, about 140 mg/m.sup.2, about 150 mg/m.sup.2, about 160
mg/m.sup.2, about 170 mg/m.sup.2, about 180 mg/m.sup.2, about 190
mg/m.sup.2, about 200 mg/m.sup.2, about 210 mg/m.sup.2, about 220
mg/m.sup.2, about 230 mg/m.sup.2, about 240 mg/m.sup.2, about 250
mg/m.sup.2, about 260 mg/m.sup.2, about 270 mg/m.sup.2, about 280
mg/m.sup.2, about 290 mg/m.sup.2, about 300 mg/m.sup.2, about 310
mg/m.sup.2, about 320 mg/m.sup.2, about 330 mg/m.sup.2, about 340
mg/m.sup.2, about 350 mg/m.sup.2, about 360 mg/m.sup.2, about 370
mg/m.sup.2, about 380 mg/m.sup.2, about 390 mg/m.sup.2, about 400
mg/m.sup.2, about 410 mg/m.sup.2, about 420 mg/m.sup.2, about 430
mg/m.sup.2, about 440 mg/m.sup.2, about 450 mg/m.sup.2, about 460
mg/m.sup.2, about 470 mg/m.sup.2, about 480 mg/m.sup.2, about 490
mg/m.sup.2, or about 500 mg/m.sup.2.
[0158] In a particular embodiment, dacarbazine is administered
intravenously.
[0159] In one embodiment, dacarbazine is administered intravenously
to a subject at a dose ranging from about 150 mg/m.sup.2 to about
250 mg/m.sup.2.
[0160] In another embodiment, dacarbazine is administered
intravenously to a subject once per day for five consecutive days
at a dose ranging from about 150 mg/m.sup.2 to about 250
mg/m.sup.2.
[0161] In a specific embodiment, dacarbazine is administered
intravenously to a subject once per day for five consecutive days
at a dose ranging from about 150 mg/m.sup.2 to about 250 mg/m.sup.2
on days 1-5, then again intravenously once per day for five
consecutive days on days 28-32 at a dose ranging from about 150
mg/m.sup.2 to about 250 mg/m.sup.2, then again intravenously once
per day for five consecutive days on days 55-59 at a dose ranging
from about 150 mg/m.sup.2 to about 250 mg/m.sup.2.
[0162] In one embodiment, dacarbazine is administered once
intravenously to a subject at a dose ranging from about 150
mg/m.sup.2 to about 250 mg/m.sup.2.
[0163] In one embodiment, the other anticancer agent is a
Topoisomerase I inhibitor, such as etoposide, teniposide,
topotecan, irinotecan, 9-aminocamptothecin, camptothecin, or
crisnatol.
[0164] In a specific embodiment, the other anticancer agent is
irinotecan.
[0165] Irinotecan can be administered to a subject at dosages
ranging from about 50 mg/m.sup.2 (of a subject's body surface area)
to about 150 mg/m.sup.2 and from about 75 mg/m.sup.2 to about 150
mg/m.sup.2. In specific embodiments, the dosages of irinotecan are
about 10 mg/m.sup.2, about 1 mg/m.sup.2, about 5 mg/m.sup.2, about
10 mg/m.sup.2, about 20 mg/m.sup.2, about 30 mg/m.sup.2, about 40
mg/m.sup.2, about 50 mg/m.sup.2, about 60 mg/m.sup.2, about 70
mg/m.sup.2, about 80 mg/m.sup.2, about 90 mg/m.sup.2, about 100
mg/m.sup.2, about 110 mg/m.sup.2, about 120 mg/m.sup.2, about 130
mg/m.sup.2, about 140 mg/m.sup.2, about 150 mg/m.sup.2, about 160
mg/m.sup.2, about 170 mg/m.sup.2, about 180 mg/m.sup.2, about 190
mg/m.sup.2, about 200 mg/m.sup.2, about 210 mg/m.sup.2, about 220
mg/m.sup.2, about 230 mg/m.sup.2, about 240 mg/m.sup.2, about 250
mg/m.sup.2, about 260 mg/m.sup.2, about 270 mg/m.sup.2, about 280
mg/m.sup.2, about 290 mg/m.sup.2, about 300 mg/m.sup.2, about 310
mg/m.sup.2, about 320 mg/m.sup.2, about 330 mg/m.sup.2, about 340
mg/m.sup.2, about 350 mg/m.sup.2, about 360 mg/m.sup.2, about 370
mg/m.sup.2, about 380 mg/m.sup.2, about 390 mg/m.sup.2, about 400
mg/m.sup.2, about 410 mg/m.sup.2, about 420 mg/m.sup.2, about 430
mg/m.sup.2, about 440 mg/m.sup.2, about 450 mg/m.sup.2, about 460
mg/m.sup.2, about 470 mg/m.sup.2, about 480 mg/m.sup.2, about 490
mg/m.sup.2, or about 500 mg/m.sup.2.
[0166] In a particular embodiment, irinotecan is administered
intravenously.
[0167] In one embodiment, irinotecan is administered intravenously
to a subject at a dose ranging from about 50 mg/m.sup.2 to about
150 mg/m.sup.2.
[0168] In another embodiment, irinotecan is administered
intravenously to a subject once per day for five consecutive days
at a dose ranging from about 50 mg/m.sup.2 to about 150
mg/m.sup.2.
[0169] In a specific embodiment, irinotecan is administered
intravenously to a subject once per day for five consecutive days
at a dose ranging from about 50 mg/m.sup.2 to about 150 mg/m.sup.2
on days 1-5, then again intravenously once per day for five
consecutive days on days 28-32 at a dose ranging from about 50
mg/m.sup.2 to about 150 mg/m.sup.2, then again intravenously once
per day for five consecutive days on days 55-59 at a dose ranging
from about 50 mg/m.sup.2 to about 150 mg/m.sup.2.
[0170] In one embodiment, the invention provides administration of
an effective amount of: (i) a Tetracyclic Amino Compound or a
Tetracyclic Carboxamido Compound and (ii) one or more other
anticancer agents.
[0171] In one embodiment, (i) a Tetracyclic Amino Compound or a
Tetracyclic Carboxamido Compound and (ii) one or more other
anticancer agents are administered in doses commonly employed when
such agents are used as monotherapy for the treatment of
cancer.
[0172] In another embodiment, (i) a Tetracyclic Amino Compound or a
Tetracyclic Carboxamido Compound and (ii) one or more other
anticancer agents act synergistically and are administered in doses
that are less than the doses commonly employed when such agents are
used as monotherapy for the treatment of cancer.
[0173] The dosage of the (i) Tetracyclic Amino Compound or the
Tetracyclic Carboxamido Compound and (ii) one or more other
anticancer agents administered as well as the dosing schedule can
depend on various parameters, including, but not limited to, the
cancer being treated, the patient's general health, and the
administering physician's discretion.
[0174] In one embodiment, the other anticancer agent is
O-6-benzylguanine.
[0175] In another embodiment, the other anticancer agent is
O-6-benzylguanine and temozolomide.
[0176] In another embodiment, the other anticancer agent is
O-6-benzylguanine and procarbazine.
[0177] In still another embodiment, the other anticancer agent is
O-6-benzylguanine and dacarbazine.
4.5.10.3 Multi-Therapy for Cancer
[0178] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can be administered to a subject that has
undergone or is currently undergoing one or more additional
anticancer therapies including, but not limited to, surgery,
radiation therapy, or immunotherapy, such as cancer vaccines.
[0179] In one embodiment, the invention provides methods for
treating or preventing cancer comprising administering to a subject
in need thereof (a) an amount of a Tetracyclic Amino Compound or a
Tetracyclic Carboxamido Compound effective to treat or prevent
cancer; and (b) another anticancer therapy including, but not
limited to, surgery, radiation therapy, or immunotherapy, such as a
cancer vaccine.
[0180] In one embodiment, the other anticancer therapy is radiation
therapy.
[0181] In another embodiment, the other anticancer therapy is
surgery.
[0182] In still another embodiment, the other anticancer therapy is
immunotherapy.
[0183] In a specific embodiment, the present methods for treating
or preventing cancer comprise administering (i) an effective amount
of a Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound
and (ii) radiation therapy. The radiation therapy can be
administered concurrently with, prior to, or subsequent to the
Tetracyclic Amino Compound or the Tetracyclic Carboxamido Compound,
in one embodiment at least an hour, five hours, 12 hours, a day, a
week, a month, in another embodiment several months (e.g., up to
three months), prior or subsequent to administration of the
Tetracyclic Amino Compound or the Tetracyclic Carboxamido
Compounds.
[0184] Where the other anticancer therapy is radiation therapy, any
radiation therapy protocol can be used depending upon the type of
cancer to be treated. For example, but not by way of limitation,
X-ray radiation can be administered; in particular, high-energy
megavoltage (radiation of greater that 1 MeV energy) can be used
for deep tumors, and electron beam and orthovoltage X-ray radiation
can be used for skin cancers. Gamma-ray emitting radioisotopes,
such as radioactive isotopes of radium, cobalt and other elements,
can also be administered.
[0185] Additionally, the invention provides methods of treatment of
cancer using a Tetracyclic Amino Compound or a Tetracyclic
Carboxamido Compound as an alternative to chemotherapy or radiation
therapy where the chemotherapy or the radiation therapy results in
negative side effects in the subject being treated. The subject
being treated can, optionally, be treated with another anticancer
therapy such as surgery, radiation therapy, or immunotherapy.
[0186] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can also be used in vitro or ex vivo, such as
for the treatment of certain cancers, including, but not limited to
leukemias and lymphomas, such treatment involving autologous stem
cell transplants. This can involve a process in which the subject's
autologous hematopoietic stem cells are harvested and purged of all
cancer cells, the subject's remaining bone-marrow cell population
is then eradicated via the administration of a Tetracyclic Amino
Compound or a Tetracyclic Carboxamido Compound and/or radiation,
and the resultant stem cells are infused back into the subject.
Supportive care can be subsequently provided while bone marrow
function is restored and the subject recovers.
4.6 Therapeutic/Prophylactic Administration and Compositions of the
Invention
[0187] Due to their activity, The Tetracyclic Amino Compounds and
the Tetracyclic Carboxamido Compounds are advantageously useful in
veterinary and human medicine. As described above, The Tetracyclic
Amino Compounds or the Tetracyclic Carboxamido Compounds are useful
for treating or preventing a Condition in a subject in need
thereof.
[0188] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can be administered in amounts that are
effective to treat or prevent a Condition in a subject.
[0189] When administered to a subject, The Tetracyclic Amino
Compounds or the Tetracyclic Carboxamido Compounds can be
administered as a component of a composition that comprises a
physiologically acceptable carrier or vehicle. The present
compositions, which comprise a Tetracyclic Amino Compound or a
Tetracyclic Carboxamido Compound, can be administered orally. The
Tetracyclic Amino Compounds or the Tetracyclic Carboxamido
Compounds can also be administered by any other convenient route,
for example, by infusion or bolus injection, by absorption through
epithelial or mucocutaneous linings (e.g., oral, rectal, and
intestinal mucosa) and can be administered together with another
biologically active agent. Administration can be systemic or local.
Various delivery systems are known, e.g., encapsulation in
liposomes, microparticles, microcapsules, capsules, and can be
administered.
[0190] Methods of administration include, but are not limited to,
intradermal, intramuscular, intraperitoneal, intravenous,
subcutaneous, intranasal, epidural, oral, sublingual,
intracerebral, intravaginal, transdermal, rectal, by inhalation, or
topical, particularly to the ears, nose, eyes, or skin. In some
instances, administration will result in the release of a
Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound
into the bloodstream.
[0191] In one embodiment, The Tetracyclic Amino Compounds or the
Tetracyclic Carboxamido Compounds are administered orally.
[0192] In other embodiments, it can be desirable to administer the
Tetracyclic Amino Compounds or the Tetracyclic Carboxamido
Compounds locally. This can be achieved, for example, and not by
way of limitation, by local infusion during surgery, topical
application, e.g., in conjunction with a wound dressing after
surgery, by injection, by means of a catheter, by means of a
suppository or enema, or by means of an implant, said implant being
of a porous, non-porous, or gelatinous material, including
membranes, such as sialastic membranes, or fibers.
[0193] In certain embodiments, it can be desirable to introduce the
Tetracyclic Amino Compounds or the Tetracyclic Carboxamido
Compounds into the central nervous system or gastrointestinal tract
by any suitable route, including intraventricular, intrathecal, and
epidural injection, and enema. Intraventricular injection can be
facilitated by an intraventricular catheter, for example, attached
to a reservoir, such as an Ommaya reservoir.
[0194] Pulmonary administration can also be employed, e.g., by use
of an inhaler of nebulizer, and formulation with an aerosolizing
agent, or via perfusion in a fluorocarbon oar, synthetic pulmonary
surfactant. In certain embodiments, the Tetracyclic Amino Compounds
or the Tetracyclic Carboxamido Compounds can be formulated as a
suppository, with traditional binders and excipients such as
triglycerides.
[0195] In another embodiment The Tetracyclic Amino Compounds or the
Tetracyclic Carboxamido Compounds can be delivered in a vesicle, in
particular a liposome (see Langer, Science 249:1527-1533 (1990) and
Treat or prevent et al., Liposomes in Therapy of Infectious Disease
and Cancer 317-327 and 353-365 (1989)).
[0196] In yet another embodiment the Tetracyclic Amino Compounds or
the Tetracyclic Carboxamido Compounds can be delivered in a
controlled-release system or sustained-release system (see, e.g.,
Goodson, in Medical Applications of Controlled Release, supra, vol.
2, pp. 115-138 (1984)). Other controlled or sustained-release
systems discussed in the review by Langer, Science 249:1527-1533
(1990) can be used. In one embodiment a pump can be used (Langer,
Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng.
14:201 (1987); Buchwald et al., Surgery 88:507 (1980); and Saudek
et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment
polymeric materials can be used (see Medical Applications of
Controlled Release (Langer and Wise eds., 1974); Controlled Drug
Bioavailability, Drug Product Design and Performance (Smolen and
Ball eds., 1984); Ranger and Peppas, J. Macromol. Sci. Rev.
Macromol. Chem. 2:61 (1983); Levy et al., Science 228:190 (1935);
During et al., Ann. Neural. 25:351 (1989); and Howard et al., J.
Neurosurg. 71:105 (1989)).
[0197] In yet another embodiment a controlled- or sustained-release
system can be placed in proximity of a target of the Tetracyclic
Amino Compounds or the Tetracyclic Carboxamido Compounds, e.g., the
spinal column, brain, skin, lung, or gastrointestinal tract, thus
requiring only a fraction of the systemic dose.
[0198] The present compositions can optionally comprise a suitable
amount of a pharmaceutically acceptable excipient so as to provide
the form for proper administration to the subject.
[0199] Such pharmaceutical excipients can be liquids, such as water
and oils, including those of petroleum, animal, vegetable, or
synthetic origin, such as peanut oil, soybean oil, mineral oil,
sesame oil and the like. The pharmaceutical excipients can be
saline, gum acacia; gelatin, starch paste, talc, keratin, colloidal
silica, urea and the like. In addition, auxiliary, stabilizing,
thickening, lubricating, and coloring agents can be used. In one
embodiment the pharmaceutically acceptable excipients are sterile
when administered to a subject. Water is a particularly useful
excipient when the Tetracyclic Amino Compound or the Tetracyclic
Carboxamido Compound is administered intravenously. Saline
solutions and aqueous dextrose and glycerol solutions can also be
employed as liquid excipients, particularly for injectable
solutions. Suitable pharmaceutical excipients also include starch,
glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,
silica gel, sodium stearate, glycerol monostearate, talc, sodium
chloride, dried skim milk, glycerol, propylene, glycol, water,
ethanol and the like. The present compositions, if desired, can
also contain minor amounts of wetting or emulsifying agents, or pH
buffering agents.
[0200] The present compositions can take the form of solutions,
suspensions, emulsion, tablets, pills; pellets, capsules, capsules
containing liquids, powders, sustained-release formulations,
suppositories, emulsions. aerosols, sprays, suspensions, or any
other form suitable for use. In one embodiment the composition is
in the form of a capsule (see e.g. U.S. Pat. No. 5,698,155). Other
examples of suitable pharmaceutical excipients are described in
Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro
eds., 19th ed. 1995), incorporated herein by reference.
[0201] In one embodiment the Tetracyclic Amino Compounds or the
Tetracyclic Carboxamido Compounds are formulated in accordance with
routine procedures as a composition adapted for oral administration
to human beings. Compositions for oral delivery can be in the form
of tablets, lozenges, aqueous or oily suspensions, granules,
powders, emulsions, capsules, syrups, or elixirs for example.
Orally administered compositions can contain one or more agents,
for example, sweetening agents such as fructose, aspartame or
saccharin; flavoring agents such as peppermint, oil of wintergreen,
or cherry; coloring agents; and preserving agents, to provide a
pharmaceutically palatable preparation. Moreover, where in tablet
or pill form, the compositions can be coated to delay
disintegration and absorption in the gastrointestinal tract thereby
providing a sustained action over an extended period of time.
Selectively permeable membranes surrounding an osmotically active
driving a Tetracyclic Amino Compound or a Tetracyclic Carboxamido
Compound are also suitable for orally administered compositions. In
these latter platforms, fluid from the environment surrounding the
capsule is imbibed by the driving compound, which swells to
displace the agent or agent composition through an aperture. These
delivery platforms can provide an essentially zero order delivery
profile as opposed to the spiked profiles of immediate release
formulations. A time-delay material such as glycerol monostearate
or glycerol stearate can also be used. Oral compositions can
include standard excipients such as mannitol, lactose, starch,
magnesium stearate, sodium saccharin, cellulose, and magnesium
carbonate. In one embodiment the excipients are of pharmaceutical
grade.
[0202] In another embodiment the Tetracyclic Amino Compounds or the
Tetracyclic Carboxamido Compounds can be formulated for intravenous
administration. Typically, compositions for intravenous
administration comprise sterile isotonic aqueous buffer. Where
necessary, the compositions can also include a solubilizing agent.
Compositions for intravenous administration can optionally include
a local anesthetic such as lignocaine to lessen pain at the site of
the injection. Generally, the ingredients are supplied either
separately or mixed together in unit dosage form, for example, as a
dry lyophilized-powder or water free concentrate in a hermetically
sealed container such as an ampule or sachette indicating the
quantity of active agent. Where the Tetracyclic Amino Compounds or
the Tetracyclic Carboxamido Compounds are to be administered by
infusion, they can be dispensed, for example, with an infusion
bottle containing sterile pharmaceutical grade water or saline.
Where the Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds are administered by injection, an ampule of
sterile water for injection or saline can be provided so that the
ingredients can be mixed prior to administration.
[0203] The Tetracyclic Amino Compounds and the Tetracyclic
Carboxamido Compounds can be administered by controlled-release or
sustained-release means or by delivery devices that are well known
to those of ordinary skill in the art. Examples include, but are
not limited to, those described in U.S. Pat. Nos. 3,845,770;
3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595;
5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and
5,733,556, each of which is incorporated herein by reference. Such
dosage forms can be used to provide controlled- or
sustained-release of one or more active ingredients using, for
example, hydropropylmethyl cellulose, other polymer matrices, gels,
permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, microspheres, or a combination thereof
to provide the desired release profile in varying proportions.
Suitable controlled- or sustained-release formulations known to
those skilled in the art, including those described herein, can be
readily selected for use with the active ingredients of the
invention. The invention thus encompasses single unit dosage forms
suitable for oral administration such as, but not limited to,
tablets, capsules, gelcaps, and caplets that are adapted for
controlled- or sustained-release.
[0204] In one embodiment a controlled- or sustained-release
composition comprises a minimal amount of a Tetracyclic Amino
Compound or a Tetracyclic Carboxamido Compound to treat or prevent
the Condition in a minimal amount of time. Advantages of
controlled- or sustained-release compositions include extended
activity of the drug, reduced dosage frequency, and increased
subject compliance. In addition, controlled- or sustained-release
compositions can favorably affect the time of onset of action or
other characteristics, such as blood levels of the Tetracyclic
Amino Compound or the Tetracyclic Carboxamido Compound, and can
thus reduce the occurrence of adverse side effects.
[0205] Controlled- or sustained-release compositions can initially
release an amount of a Tetracyclic Amino Compound or a Tetracyclic
Carboxamido Compound that promptly produces the desired therapeutic
or prophylactic effect, and gradually and continually release other
amounts of the Tetracyclic Amino Compound or the Tetracyclic
Carboxamido Compound to maintain this level of therapeutic or
prophylactic effect over an extended period of time. To maintain a
constant level of the Tetracyclic Amino Compound or the Tetracyclic
Carboxamido Compound in the body, the Tetracyclic Amino Compound or
the Tetracyclic Carboxamido Compound can be released from the
dosage form at a rate that will replace the amount of Tetracyclic
Amino Compound or Tetracyclic Carboxamido Compound being
metabolized and excreted from the body. Controlled- or
sustained-release of an active ingredient can be stimulated by
various conditions, including but not limited to, changes in pH,
changes in temperature, concentration or availability of enzymes,
concentration or availability of water, or other physiological
conditions or compounds.
[0206] The amount of the Tetracyclic Amino Compound or the
Tetracyclic Carboxamido Compound that is effective in the treatment
or prevention of a Condition can be determined by standard clinical
techniques. In addition, in vitro or in vivo assays can optionally
be employed to help identify optimal dosage ranges. The precise
dose to be employed can also depend on the route of administration,
and the seriousness of the condition being treated and can be
decided according to the judgment of the practitioner and each
subject's circumstances in view of, e.g., published clinical
studies. Suitable effective dosage amounts, however, range from
about 10 micrograms to about 5 grams about every 4 h, although they
are typically about 500 mg or less per every 4 hours. In one
embodiment the effective dosage is about 0.01 mg, 0.5 mg, about 1
mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about
400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg,
about 900 mg, about 1 g, about 1.2 g, about 1.4 g, about 1.6 g,
about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g,
about 2.8 g, about 3.0 g, about 3.2 g, about 3.4 g, about 3.6 g,
about 3.8 g, about 4.0 g, about 4.2 g, about 4.4 g, about 4.6 g,
about 4.8 g, and about 5.0 g, every 4 hours. Equivalent dosages can
be administered over various time periods including, but not
limited to, about every 2 hours, about every 6 hours, about every 8
hours, about every 12 hours, about every 24 hours, about every 36
hours, about every 48 hours, about every 72 hours, about every
week, about every two weeks, about every three weeks, about every
month, and about every two months. The effective dosage amounts
described herein refer to total amounts administered; that is, if
more than one Tetracyclic Amino Compound or Tetracyclic Carboxamido
Compound is administered, the effective dosage amounts correspond
to the total amount administered.
[0207] Compositions can be prepared according to conventional
mixing, granulating or coating methods, respectively, and the
present compositions can contain, in one embodiment, from about
0.1% to about 99%; and in another embodiment from about 1% to about
70% of the Tetracyclic Amino Compound or the Tetracyclic
Carboxamido Compound by weight or volume.
[0208] The dosage regimen utilizing the Tetracyclic Amino Compound
or the Tetracyclic Carboxamido Compound can be selected in
accordance with a variety of factors including type, species, age,
weight, sex and medical condition of the subject; the severity of
the condition to be treated; the route of administration; the renal
or hepatic function of the subject; and the particular Tetracyclic
Amino Compound or Tetracyclic Carboxamido Compound employed. A
person skilled in the art can readily determine the effective
amount of the drug useful for treating or preventing the
Condition.
[0209] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can be administered in a single daily dose,
or the total daily dosage can be administered in divided doses of
two, three or four times daily. Furthermore, the Tetracyclic Amino
Compounds or the Tetracyclic Carboxamido Compounds can be
administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal routes, using those forms
of transdermal skin patches well known to those of ordinary skill
in that art. To be administered in the form of a transdermal
delivery system, the dosage administration can be continuous rather
than intermittent throughout the dosage regimen. Other illustrative
topical preparations include creams, ointments, lotions, aerosol
sprays and gels, wherein the concentration of Tetracyclic Amino
Compound or Tetracyclic Carboxamido Compound ranges from about 0.1%
to about 15%, w/w or w/v.
[0210] In one embodiment, the compositions comprise an amount of
(i) a Tetracyclic Amino Compound or a Tetracyclic Carboxamido
Compound and (ii) the other anticancer agent which together are
effective to treat or prevent cancer. In another embodiment, the
amount of (i) a Tetracyclic Amino Compound or a Tetracyclic
Carboxamido Compound and (ii) the other anticancer agent is at
least about 0.01% of the combined combination chemotherapy agents
by weight of the composition. When intended for oral
administration, this amount can be varied from about 0.1% to about
80% by weight of the composition. Some oral compositions can
comprise from about 4% to about 50% of combined amount of (i) a
Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound
and (ii) the other anticancer agent by weight of the composition.
Other compositions of the present invention are prepared so that a
parenteral dosage unit contains from about 0.01% to about 2% by
weight of the composition.
[0211] The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds can be assayed in vitro or in vivo for the
desired therapeutic or prophylactic activity prior to use in
humans. Animal model systems can be used to demonstrate safety and
efficacy.
[0212] The present methods for treating or preventing a Condition
in a subject in need thereof can further comprise administering
another prophylactic or therapeutic agent to the subject being
administered a Tetracyclic Amino Compound or a Tetracyclic
Carboxamido Compound. In one embodiment the other prophylactic or
therapeutic agent is administered in an effective amount. The other
prophylactic or therapeutic agent includes, but is not limited to,
an anti-inflammatory agent, an anti-renal failure agent, an
anti-diabetic agent, and anti-cardiovascular disease agent, an
antiemetic agent, a hematopoietic colony stimulating factor, an
anxiolytic agent, and an analgesic agent.
[0213] In one embodiment, the other prophylactic or therapeutic
agent is an agent useful for reducing any potential side effect of
a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound.
Such potential side effects include, but are not limited to,
nausea, vomiting, headache, low white blood cell count, low red
blood cell count, low platelet count, headache, fever, lethargy,
muscle aches, general pain, bone pain, pain at an injection site,
diarrhea, neuropathy, pruritis, mouth sores, alopecia, anxiety or
depression.
[0214] In one embodiment, the Tetracyclic Amino Compound or
Tetracyclic Carboxamido Compound can be administered prior to,
concurrently with, or after an anti-inflammatory agent, or on the
same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours
or 72 hours of each other.
[0215] In another embodiment, the Tetracyclic Amino Compound or
Tetracyclic Carboxamido Compound can be administered prior to,
concurrently with, or after an anti-renal failure agent, or on the
same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours
or 72 hours of each other.
[0216] In still another embodiment, the Tetracyclic Amino Compound
or Tetracyclic Carboxamido Compound can be administered prior to,
concurrently with, or after an anti-diabetic agent, or on the same
day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72
hours of each other.
[0217] In yet another embodiment, the Tetracyclic Amino Compound or
Tetracyclic Carboxamido Compound can be administered prior to,
concurrently with, or after an anti-cardiovascular disease agent,
or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours,
48 hours or 72 hours of each other.
[0218] In a further embodiment, the Tetracyclic Amino Compound or
Tetracyclic Carboxamido Compound can be administered prior to,
concurrently with, or after an antiemetic agent, or on the same
day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72
hours of each other.
[0219] In another embodiment, the Tetracyclic Amino Compound or
Tetracyclic Carboxamido Compound can be administered prior to,
concurrently with, or after a hematopoietic colony stimulating
factor, or on the same day, or within 1 hour, 2 hours, 12 hours, 24
hours, 48 hours, 72 hours, 1 week, 2 weeks, 3 weeks or 4 weeks of
each other.
[0220] In still embodiment, the Tetracyclic Amino Compound or
Tetracyclic Carboxamido Compound can be administered prior to,
concurrently with, or after an opioid or non-opioid analgesic
agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24
hours, 48 hours or 72 hours of each other.
[0221] In yet another embodiment, the Tetracyclic Amino Compound or
Tetracyclic Carboxamido Compound can be administered prior to,
concurrently with, or after an anxiolytic agent, or on the same
day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72
hours of each other.
[0222] Effective amounts of the other prophylactic or therapeutic
agents are well known to those skilled in the art. However, it is
well within the skilled artisan's purview to determine the other
prophylactic or therapeutic agent's optimal effective amount range.
In one embodiment of the invention, where another prophylactic or
therapeutic agent is administered to a subject, the effective
amount of the Tetracyclic Amino Compound or the Tetracyclic
Carboxamido Compound is less than its effective amount would be
where the other prophylactic or therapeutic agent is not
administered. In this case, without being bound by theory, it is
believed that The Tetracyclic Amino Compounds or the Tetracyclic
Carboxamido Compounds and the other prophylactic or therapeutic
agent act synergistically to treat or prevent a Condition.
[0223] Anti-inflammatory agents useful in the methods of the
present invention include but are not limited to
adrenocorticosteroids, such as cortisol, cortisone,
fludrocortisone, prednisone, prednisolone,
6.alpha.-methylprednisolone, triamcinolone, betamethasone, and
dexamethasone; and non-steroidal anti-inflammatory agents (NSAIDs),
such as aspirin, acetaminophen, indomethacin, sulindac, tolmetin,
diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen,
ketoprofen, fenoprofen, oxaprozin, mefenamic acid, meclofenamic
acid, piroxicam, meloxicam, nabumetone, rofecoxib, celecoxib,
etodolac, and nimesulide.
[0224] Anti-renal failure agents useful in the methods of the
present invention include include but are not limited to ACE
(angiotensin-converting enzyme) inhibitors, such as captopril,
enalaprilat, lisinopril, benazepril, fosinopril, trandolapril,
quinapril, and ramipril; diuretics, such as mannitol, glycerin,
furosemide, toresemide, tripamide, chlorothiazide,
methyclothiazide, indapamide, amiloride, and spironolactone; and
fibric acid agents, such as clofibrate, gemfibrozil, fenofibrate,
ciprofibrate, and bezafibrate.
[0225] Anti-diabetic agents useful in the methods of the present
invention include but are not limited to glucagons; somatostatin;
diazoxide; sulfonylureas, such as tolbutamide, acetohexamide,
tolazamide, chloropropamide, glybenclamide, glipizide, gliclazide,
and glimepiride; insulin secretagogues, such as repaglinide, and
nateglinide; biguanides, such as metformin and phenformin;
thiazolidinediones, such as pioglitazone, rosiglitazone, and
troglitazone; and .alpha.-glucosidase inhibitors, such as acarbose
and miglitol.
[0226] Anti-cardiovascular disease agents useful in the methods of
the present invention include but are not limited to carnitine;
thiamine; and muscarinic receptor antagonists, such as atropine,
scopolamine, homatropine, tropicamide, pirenzipine, ipratropium,
tiotropium, and tolterodine.
[0227] Antiemetic agents useful in the methods of the present
invention include, but are not limited to, metoclopromide,
domperidone, prochlorperazine, promethazine, chlorpromazine,
trimethobenzamide, ondansetron, granisetron, hydroxyzine,
acetylleucine monoethanolamine, alizapride, azasetron,
benzquinamide, bietanautine, bromopride, buclizine, clebopride,
cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,
methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,
scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine,
thioproperazine, tropisetron, and mixtures thereof.
[0228] Hematopoietic colony stimulating factors useful in the
methods of the present invention include, but are not limited to,
filgrastim, sargramostim, molgramostim and epoietin alfa.
[0229] Opioid analgesic agents useful in the methods of the present
invention include, but are not limited to, morphine, heroin,
hydromorphone, hydrocodone, oxymorphone, oxycodone, metopon,
apomorphine, normorphine, etorphine, buprenorphine, meperidine,
lopermide, anileridine, ethoheptazine, piminidine, betaprodine,
diphenoxylate, fentanil, sufentanil, alfentanil, remifentanil,
levorphanol, dextromethorphan, phenazocine, pentazocine,
cyclazocine, methadone, isomethadone and propoxyphene.
[0230] Non-opioid analgesic agents useful in the methods of the
present invention include, but are not limited to, aspirin,
celecoxib, rofecoxib, diclofinac, diflusinal, etodolac, fenoprofen,
flurbiprofen, ibuprofen, ketoprofen, indomethacin, ketorolac,
meclofenamate, mefanamic acid, nabumetone, naproxen, piroxicam and
sulindac.
[0231] Anxiolytic agents useful in the methods of the present
invention include, but are not limited to, buspirone, and
benzodiazepines such as diazepam, lorazepam, oxazapam,
chlorazepate, clonazepam, chlordiazepoxide and alprazolam.
4.7 Kits
[0232] The invention encompasses kits that can simplify the
administration of a Tetracyclic Amino Compound or a Tetracyclic
Carboxamido Compound to a subject.
[0233] A typical kit of the invention comprises a unit dosage form
of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido
Compound. In one embodiment the unit dosage form is a container,
which can be sterile, containing an effective amount of a
Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound
and a physiologically acceptable carrier or vehicle. The kit can
further comprise a label or printed instructions instructing the
use of the Tetracyclic Amino Compound or the Tetracyclic
Carboxamido Compound to treat or prevent a Condition. The kit can
also further comprise a unit dosage form of another prophylactic or
therapeutic agent, for example, a container containing an effective
amount of the other prophylactic or therapeutic agent. In one
embodiment the kit comprises a container containing an effective
amount of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido
Compound and an effective amount of another prophylactic or
therapeutic agent. Examples of other prophylactic or therapeutic
agents include, but are not limited to, those listed above.
[0234] Kits of the invention can further comprise a device that is
useful for administering the unit dosage forms. Examples of such a
device include, but are not limited to, a syringe, a drip bag, a
patch, an inhaler, and an enema bag.
[0235] The invention is further described in the following
examples, which do not limit the scope of the invention described
in the claims. The following examples can demonstrate the
usefulness of the Tetracyclic Amino Compounds and Tetracyclic
Carboxamido Compounds for treating or preventing a Condition.
5. EXAMPLES
Example 1
a) General Methods
[0236] Proton nuclear magnetic resonance (.sup.1H NMR) spectra were
obtained from Varian 300 MHz spectrophotometer and chemical shift
is reported in parts per million, .delta.. Thin layer
chromatography, TLC, was carried out on precoated TLC plates with
silica gel 60 F-254 and preparative TLC on precoated Whatman 60A
TLC plates. All intermediates and final compounds were
characterized on the basis of .sup.1H NMR.
b) Methyl
5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline-10-carboxylate
(17a)
##STR00057##
[0238] A mixture of methyl 2-bromomethyl-3-cyanobenzoate (14.1 g,
55.5 mmol) and homophthalic anhydride (22.5 g, 138.8 mmol) in
acetonitrile (150 ml) was stirred at room temperature, and a
solution of triethylamine (23.2 ml) in acetonitrile (100 ml) was
added dropwise to the mixture over the period of 1 h. After the
completion of addition, the resultant suspension was refluxed for 4
hours. The reaction mixture was then cooled down to room
temperature and filtered. The filtered solid was washed thoroughly
with acetonitrile (100 ml) and ethanol (2.times.100 ml) and dried
under vacuum at 50.degree. C. Compound 17a was obtained in 81%
yield (13.1 g). .sup.1H NMR (DMSO-d.sub.6): .delta. 12.21 (s, 1H);
8.20 (m, 2H); 7.83 (d, J=7.5 Hz, 1H); 7.71 (m, 2H); 7.47 (m, 2H);
4.07 (s, 2H); 3.89 (s, 3H).
c) Methyl
5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline-9-carboxylate
(18a)
##STR00058##
[0240] Compound 18a was prepared from methyl
3-bromomethyl-4-cyanobenzoate in 65% yield. The reaction was
carried out according to the procedure for preparing methyl
5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline-10-carboxylate
(17a). .sup.1H NMR (DMSO-d.sub.6): .delta. 12.35 (s, 1H); 8.25 (d,
J=8.1 Hz, 1H); 8.11 (s, 1H); 8.06 (d, J=7.8 Hz, 1H); 7.98 (d, J=8.1
Hz, 1H); 7.75 (m, 2H); 7.49 (m, 1H); 3.95 (s, 2H); 3.85 (s,
3H).
d) 5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline-10-carboxylic
acid (18b)
##STR00059##
[0242] A suspension of Compound 18a in a mixture of methanol and 1M
NaOH solution was refluxed for 1 h. Additional water was added, and
the resultant mixture was refluxed for another 1 h. The resultant
clear solution was cooled to room temperature and 1M HCl solution
was added under stirring. The resultant solid was filtered and
washed with water and methanol and dried to provide Compound 18b.
.sup.1H NMR (DMSO-d.sub.6): .delta. 12.38 (s, 1H); 8.25 (d, J=7.8
Hz, 1H); 8.11 (s, 1H); 8.04 (d, J=8.1 Hz, 1H); 7.97 (d, J=8.1 Hz,
1H); 7.76 (d, J=3.6 Hz, 2H); 7.51 (m, 1H); 3.97 (s, 2H).
e) 5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline-9-carboxylic
acid
##STR00060##
[0244] The above compound was made according to the procedure for
preparing
5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline-10-carboxylic acid
(18b), but using Compound 18a in place of Compound 17a. .sup.1H NMR
(DMSO-d.sub.6): .delta. 12.34 (s, 1H); 8.24 (d, J=8.1 Hz, 1H); 8.20
(d, J=7.5 Hz 1H); 7.88 (d, J=7.8 Hz, 1H); 7.77 (m, 2H); 7.54 (d,
J=7.8 Hz, 2H); 7.49 (d, J=8.1 Hz, 1H); 4.18 (s, 2H).
f) General Procedure for the Coupling of the Amine to the
Carboxylic Acid
[0245] A suspension of C.sub.9-- or C.sub.10--COOH and carbodiimide
in dioxane was stirred at room temperature for 10 min. The relevant
amine was added and the reaction mixture was stirred overnight at
room temperature. The resultant solid was filtered, washed with
dioxane and dried in a vacuum oven for 3 h. The following compounds
are illustrative of the synthesis of Tetracyclic Carboxamido
Compounds of Formulas (IIc) and (IId):
TABLE-US-00011 ##STR00061## C.sub.9 Position C.sub.10 Position 14a
CONH(CH.sub.2).sub.2morpholine H 14b CONH(CH.sub.2).sub.3morpholine
H 13b CONH(CH.sub.2).sub.3NMe.sub.2 H 16a H
CONH(CH.sub.2).sub.2morpholine 16b H CONH(CH.sub.2).sub.3morpholine
15a H CONH(CH.sub.2).sub.2NMe.sub.2 15b H
CONH(CH.sub.2).sub.3NMe.sub.2 Compound 14a: .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.25 (d, J = 8.1 Hz, 1 H); 8.09 (s, 1 H);
7.97 (q, J = 7.9 Hz, 2 H); 7.76 (d, J = 3.9 Hz, 2 H); 7.48 (m, 1
H); 3.94 (s, 2 H); 3.56 (t, J = 4.7 Hz, 4 H); 2.77 (t, J = 6.0 Hz,
2 H); 2.40-2.33 (m, 6 H). Compound 14b: .sup.1H NMR (DMSO-d.sub.6):
.delta. 8.24 (d, J = 8.1 Hz, 1 H); 8.07 (s, 1 H); 7.92 (m, 2 H);
7.75 (d, J = 3.6 Hz, 2 H); 7.46 (m, 1 H); 3.91 (s, 2 H); 3.54 (t, J
= 4.5 Hz, 4 H); 2.73 (t, J = 6.9 Hz, 2 H); 2.31 (m, 6 H); 1.62 (t,
J = 6.9 Hz, 2 H). Compound 13b: .sup.1H NMR (DMSO-d.sub.6): .delta.
8.23 (d, J = 8.1 Hz, 1 H); 8.06 (s, 1 H); 7.90 (m, 2 H); 7.73 (m, 2
H); 7.45 (m, 1 H); 3.89 (s, 2 H); 2.71 (t, J = 6.9 Hz, 4 H); 2.23
(t, J = 6.6 Hz, 2 H); 2.09 (s, 6 H); 1.59 (t, J = 6.9 Hz, 2 H).
Compound 16a: .sup.1H NMR (DMSO-d.sub.6): .delta. 8.23 (d, J = 8.1
Hz, 1 H); 8.03 (d, J = 7.5 Hz, 1 H); 7.80 (d, J = 7.8 Hz, 1 H);
7.74 (m, 2 H); 7.47-7.36 (m, 2 H); 4.15 (s, 2 H); 3.54 (m, 4 H);
2.78 (t, J = 6.0 Hz, 2 H); 2.41-2.30 (m, 6 H). Compound 16b:
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.22 (d, J = 7.8 Hz, 1 H); 7.98
(d, J = 7.2 Hz, 1 H); 7.79 (d, J = 7.2 Hz, 1 H); 7.71 (m, 2 H);
7.42 (m, 1 H); 7.34 (t, J = 7.8 Hz, 1 H); 4.14 (s, 2 H); 2.82 (t, J
= 6.9 Hz, 2 H); 2.29 (m, 6 H); 1.70 (t, J = 6.6 Hz, 2 H). Compound
15a: .sup.1H NMR (DMSO-d.sub.6): .delta. 8.22 (d, J = 8.1 Hz, 1 H);
8.03 (d, J = 7.2 Hz, 1 H); 7.80 (d, J = 7.8 Hz, 1 H); 7.73 (m, 2
H); 7.44 (m, 1 H); 7.37 (t, J = 8.1 Hz, 1 H); 4.14 (s, 2 H); 2.79
(t, 2 H); 2.36 (t, J = 6.0 Hz, 2 H); 2.14 (s, 6 H). Compound 15b:
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.24 (d, J = 7.8 Hz, 1 H); 8.01
(d, J = 7.2 Hz, 1 H); 7.80 (d, J = 8.1 Hz, 1 H); 7.73 (d, J = 3.3
Hz, 2 H); 7.44 (m, 1 H); 7.37 (t, J = 7.5 Hz, 1 H); 4.15 (s, 2 H);
2.77 (t, J = 6.9 Hz, 2 H); 2.26 (t, J = 6.9 Hz, 2 H); 2.10 (s, 6
H); 1.63 (t, J = 6.9 Hz, 2 H).
g) Example 2 Effect of Illustrative Tetracyclic Amino Compounds and
Tetracyclic Carboxamido Compounds on in Vitro PARS Activity
[0246] The ability of an illustrative Tetracyclic Amino Compound or
Tetracyclic Carboxamido Compound to inhibit PARS and prevent
peroxynitrite induced cytotoxicity can be demonstrated using
methods described in Virag et al., Br. J. Pharmacol. 1999,
126(3):769-77; and Immunology 1998, 94(3):345-55.
h) Cell Protection Assay
[0247] Raw murine macrophages were treated with an illustrative
Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound for
15 minutes prior to the addition of peroxynitrite (750 .mu.M) for a
further 15 minutes. For the measurement of PARS activity, the media
were removed and replaced with 0.5 ml HEPES (pH 7.5) containing
0.01% digitonin and .sup.3H-NAD (0.5 .mu.Ci ml.sup.-1, final
concentration of NAD.sup.+ in buffer is 20 nM/L) for 20 minutes.
The cells were then scraped from the wells and placed in Eppendorf
tubes containing 200 .mu.l of 50% (w/v) ice-cold trichloroacetic
acid (TCA). The tubes were then placed at 4.degree. C. After 4 hr
the tubes were centrifuged at 1800 g for 10 minutes and the
supernatant removed. The pellets were washed twice with 500 .mu.l
ice-cold 5% TCA. The pellets were solubilized in 250 .mu.l NaOH
(0.1 M) containing 2% SDS overnight at 37.degree. C. and the PARS
activity was then determined by measuring the radioactivity
incorporated using a Wallac scintillation counter. The solubilized
protein (250 .mu.l) was mixed with 5 ml of scintillant (ScintiSafe
Plus, Fisher Scientific) before being counted for 10 minutes. The
EC.sub.50 value was calculated from a dose-response curve.
TABLE-US-00012 TABLE 1 Inhibitory effect of illustrative
Isoquinoline Compounds on cell protection ##STR00062## EC.sub.50
C.sub.9 Position C.sub.10 Position .mu.M 14a
CONH(CH.sub.2).sub.2morpholine H 1.1 14b
CONH(CH.sub.2).sub.3morpholine H 1.1 13b
CONH(CH.sub.2).sub.3NMe.sub.2 H 0.9 16a H
CONH(CH.sub.2).sub.2morpholine >1.5 16b H
CONH(CH.sub.2).sub.3morpholine >1.5 15a H
CONH(CH.sub.2).sub.2NMe.sub.2 >1.5 15b H
CONH(CH.sub.2).sub.3NMe.sub.2 >1.5
i) Example 3: Effects of Tetracyclic Amino Compounds and
Tetracyclic Carboxamido Compounds in an in Vitro Model of Cell
Death
[0248] Using an in vitro, oxidant-stimulated thymocyte assay
(described, in detail, in Virag et al., Immunology 94(3):345-55,
1998), an illustrative Tetracyclic Amino Compound or Tetracyclic
Carboxamido Compound can be tested for its ability to prevent the
oxidant-induced suppression of the viability of the cells and as
such, this assay represents an in vitro model of reperfusion
related cell death in ischemic organs.
j) Example 4: Effect of Tetracyclic Amino Compounds and Tetracyclic
Carboxamido Compounds on in Vivo Models of Inflammatory
Diseases
[0249] In order to substantiate the efficacy of the compounds in
inflammatory diseases, the effect of an illustrative Tetracyclic
Amino Compound or Tetracyclic Carboxamido Compound can be
determined using a systemic inflammatory model induced by bacterial
lipopolysaccharide (LPS), which is reported to be responsible for
causing reperfusion injuries and inflammatory diseases such as
septic shock and systemic inflammatory response syndrome in animals
(see Parrillo, N. Engl. J. Med., 328:1471-1478 (1993) and Lamping,
J. Clin. Invest. 101:2065-2071 (1998).
k) Example 5: Determination of the Effect of Tetracyclic Amino
Compounds and Tetracyclic Carboxamido Compounds on in Vivo Models
of Reperfusion Injury
[0250] The efficacy of an illustrative Tetracyclic Amino Compound
or Tetracyclic Carboxamido Compound in a mouse model of ischemic
and reperfused gut can be determined according to the method
described in Liaudet et al., Shock 2000, 14(2): 134-41.
[0251] In another set of experiments, the effect of an illustrative
Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound in a
rat model of middle cerebral artery occlusion/reperfusion can be
assayed as described in Abdelkarim et al., Int J Mol Med. 2001,
7(3):255-60.
l) Example 6: Effect of Illustrative Tetracyclic Amino Compounds
and Tetracyclic Carboxamido Compounds in an in Vivo Model of
Diabetes
[0252] PARS inhibitors and PARS deficiency are known to reduce the
development of diabetes and the incidence of diabetic
complications. In order to substantiate the efficacy of an
illustrative Tetracyclic Amino Compound or Tetracyclic Carboxamido
Compound in a diabetes model, a single high-dose streptozotocin
model of diabetes can be used as conducted as described in Mabley
et al., Br J Pharmacol. 2001, 133(6):909-9; and Soriano et al., Nat
Med. 2001, 7(1): 108-13. Briefly, 160 mg/kg streptozotocin is
injected to mice treated with vehicle (control) or with an
illustrative Tetracyclic Amino Compound or Tetracyclic Carboxamido
Compound intraperitoneally (3 mg/kg) and 3 days later blood sugar
levels are determined using a blood glucose meter.
[0253] The present invention is not to be limited in scope by the
specific embodiments disclosed in the examples which are intended
as illustrations of a few aspects of the invention and any
embodiments that are functionally equivalent are within the scope
of this invention. Indeed, various modifications of the invention
in addition to those shown and described herein will become
apparent to those skilled in the art and are intended to fall
within the scope of the appended claims.
[0254] A number of references have been cited, the entire
disclosures of which have been incorporated herein in their
entirety.
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