Selected fused pyrrolocarbazoles

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Reexamination Certificate

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C548S417000

Reexamination Certificate

active

06630500

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to selected fused pyrrolocarbazoles, including pharmaceutical compositions thereof and methods of treating diseases therewith. The present invention is also directed to intermediates and processes for making these fused pyrrolocarbazoles.
BACKGROUND OF THE INVENTION
Publications cited throughout this disclosure are incorporated in their entirety herein by reference.
Various synthetic small organic molecules that are biologically active and generally known in the art as “fused pyrrolocarbazoles” have been prepared (See U.S. Pat. Nos. 5,475,110; 5,591,855; 5,594,009; and 5,616,724). In addition, U.S. Pat. No. 5,705,511 discloses fused pyrrolocarbazole compounds which possess a variety of functional pharmacological activities. The fused pyrrolocarbazoles were disclosed to be used in a variety of ways, including: enhancing the function and/or survival of cells of neuronal lineage, either singularly or in combination with neurotrophic factor(s) and/or indolocarbozoles; enhancing trophic factor-induced activity; inhibition of protein kinase C (“PKC”) activity; inhibition of trk tyrosine kinase activity; inhibition of proliferation of a prostate cancer cell-line; inhibition of the cellular pathways involved in the inflammation process; and enhancement of the survival of neuronal cells at risk of dying.
The present inventors have found that certain selected fused pyrrolocarbazoles selected from the generic formulas of U.S. Pat. No. 5,705,511 but not specifically disclosed therein possess surprising and unexpected biological activities compared to the compounds described in U.S. Pat. No. 5,705,511.
SUMMARY OF THE INVENTION
Accordingly, one object of the invention is to provide novel fused pyrrolocarbazole compounds represented by the general Formula I:
Constituent members of Formula I are disclosed in detail, infra.
Preferred fused pyrrolocarbazoles are represented by the following Formula II:
Constituent members of Formula I are disclosed in detail, infra.
The fused pyrrolocarbazoles of the present invention may be used in a variety of ways, including: inhibition of angiogenesis; antitumor agents; enhancing the function and/or survival of cells of neuronal lineage, either singularly or in combination with neurotrophic factor(s) and/or indolocarbozoles; enhancing trophic factor-induced activity; inhibition of kinases; inhibition of vascular endothelial growth factor receptor (VEGFR) kinase, preferably VEGFR2; inhibition of mixed lineage kinase (MLK); trk kinase; inhibition of platelet derived growth factor receptor (PDGFR) kinase; inhibition of NGF-stimulated trk phosphorylation; inhibition of protein kinase C (“PKC”) activity; inhibition of trk tyrosine kinase activity; inhibition of proliferation of a prostate cancer cell-line; inhibition of the cellular pathways involved in the inflammation process; and enhancement of the survival of neuronal cells at risk of dying. In addition, the fused pyrrolocarbazoles may useful for inhibition of c-met, c-kit, and mutated Flt-3 containing internal tandem duplications in the juxtamembrane domain. Because of these varied activities, the disclosed compounds find utility in a variety of settings, including research and therapeutic environments.
Another object of the present invention is to provide pharmaceutical compositions comprising a fused pyrrolocarbazole of the present invention wherein the compositions comprise a pharmaceutically acceptable excipient or carrier and a therapeutically effective amount of at least one of the compounds of the present invention, or a pharmaceutically acceptable salt or ester form thereof.
It is another object of the present invention to provide methods of treating or preventing diseases or disorders comprising administering a therapeutic or preventative effective amount of at least one of the compounds of the present invention to a subject in need thereof.
These and other objects, features and advantages of the fused pyrrolocarbazoles will be disclosed in the following detailed description of the patent disclosure.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
One embodiment of the present invention are the fused pyrrolocarbazoles represented by Formula I:
wherein:
R
1
and R
2
are the same or different and are independently selected from H, or alkyl of 1-8 carbons (inclusive), preferably an alkyl of 1-4 carbons (inclusive), substituted with OH, or —OR
4
where R
4
is an alkyl of 1-4 carbons (inclusive), aryl, preferably phenyl or naphthyl, or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and
R
3
is —CH
2
OH; —CH
2
OR
7
; —(CH
2
)
n
SR
5
; —(CH
2
)
n
S(O)
y
R
5
; —CH
2
SR
5
; or alkyl of 1-8 carbons (inclusive), preferably an alkyl of 1-4 carbons (inclusive), substituted with —OH, —OR
5
, —OR
8
, —CH
2
OR
7
, —S(O)
y
R
6
or SR
6
; and wherein
R
5
is alkyl of 1-4 carbons (inclusive), or aryl, preferably phenyl or naphthyl;
R
6
is H, alkyl of 1-4 carbons (inclusive), aryl of 6-10 carbons, preferably phenyl or naphthyl, or heteroaryl;
R
7
is H or alkyl of 1-4 carbons (inclusive);
R
8
is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;
n is an integer of 1-4 (inclusive); and
y is 1 or 2.
In certain preferred embodiments, the compounds of Formula I are those of Formula II:
wherein R
1
, R
2
, and R
3
are as defined for Formula I above.
In certain referred embodiments, R
1
is an alkyl of 1-4 carbons (inclusive), substituted with —OH or —OR
4
where R
4
is an alkyl of 1-4 carbons (inclusive), aryl, preferably phenyl or naphthyl, or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;
R
2
is H; and R
3
is —CH
2
OH; —CH
2
OR
7
; —(CH
2
)
n
SR
5
; —(CH
2
)
n
S(O)
y
R
5
; —CH
2
SR
5
; or alkyl of 1-8 carbons (inclusive), preferably an alkyl of 1-4 carbons (inclusive), substituted with —OH, —OR
5
, —OR
8
, —CH
2
OR
7
, —S(O)
y
R
6
or SR
6
;
wherein R
5
, R
6
, R
7
and R
8
are as defined for Formula I above.
In certain other preferred embodiments, R
1
is —CH
2
CH
2
CH
2
OH or —CH
2
CH
2
CH
2
OCOCH
2
N(CH
3
)
2
, R
2
is H and R
3
is —CH
2
OR
7
; wherein R
7
is alkyl of 1-4 carbons (inclusive).
In certain even further preferred embodiments the fused pyrrolocarbazoles of Formula I and Formula II are those represented in Table I:
TABLE I
Cmpd
R
1
R
2
R
3
 1
CH
2
CH
2
CH
2
OH
H
CH
2
OCH
2
CH
3
 2
CH
2
CH
2
CH
2
OH
H
CH
2
OCH
3
 3
CH
2
CH
2
CH
2
OH
H
CH
2
OCH(CH
3
)
2
 4
CH
2
CH
2
CH
2
OH
H
CH
2
OCH(CH
3
)CH
2
CH
3
 5
CH
2
CH
2
CH
2
OH
H
(S)-CH
2
OCH(CH
3
)CH
2
CH
3
 6
CH
2
CH
2
CH
2
OH
H
(R)-CH
2
OCH(CH
3
)CH
2
CH
3
 7
CH
2
CHOHCH
3
H
CH
2
OCH
2
CH
3
 8
CH
2
CH
2
CH
2
OH
H
CH
2
OCH
2
CH
2
CH
3
 9
CH
2
CH
2
CH
2
OH
H
CH
2
OCH
2
CH
2
CH
2
CH
3
10
CH
2
CH
2
CH
2
OH
H
CH(CH
3
)OCH
2
CH
3
11
CH
2
CH
2
CH
2
OH
H
(chiral) CH(CH
3
)OCH
2
CH
3
12
CH
2
CH
2
CH
2
OH
H
(chiral) CH(CH
3
)OCH
2
CH
3
13
CH
2
CH
2
CH
2
OH
H
CH(CH
3
)OCH
3
14
H
CH
2
CHOHCH
3
CH
2
OCH
2
CH
3
15
CH
2
CH
2
CH
2
OH
H
CH(CH
3
)OCH
2
CH
2
CH
2
CH
3
16
CH
2
CH
2
CH
2
OH
H
CH(CH
3
)OCH(CH
3
)
2
17
CH
2
CH
2
CH
2
OH
H
CH
2
OC(CH
3
)
3
18
CH
2
CH
2
CH
2
OCOCH
2
NH
2
H
CH
2
OCH(CH
3
)
2
19
CH
2
CH
2
CH
2
OCOCH(NH
2
)CH
2

H
CH
2
OCH(CH
3
)
2
CH
2
CH
2
CH
2
NH
2
20
CH
2
CH
2
CH
2
OCOCH
2
CH
2
NH
2
H
CH
2
OCH(CH
3
)
2
21
CH
2
CH
2
CH
2
OCOCH
2
CH
2

H
CH
2
OCH(CH
3
)
2
CH
2
N(CH
3
)
2
22
CH
2
CH
2
CH
2
OCOCH
2
N(CH
3
)
2
H
CH
2
OCH(CH
3
)
2
23
CH
2
CH
2
CH
2
OCOCH
2
CH
2
CH
2

H
CH
2
OCH(CH
3
)
2
CH
2
CH
2
NH
2
24
CH
2
CH
2
OH
H
CH
2
SCH
2
CH
3
25
CH
2
CH
2
CH
2
OH
H
CH
2
SCH
2
CH
3
26
CH
2
CH
2
CH
2
OH
H
CH
2
S(O)CH(CH
3
)
2
27
CH
2
CH
2
CH
2
OH
H
CH
2
SCH(CH
3
)
2
28
CH
2
CH
2
OH
H
CH
2
OH
29
CH
2
CH
2
CH
2
OH
H
CH
2
OH
30
H
H
CH
2
OH
31
H
H
CH
2
OCH
2
CH
3
32
H
H
CH
2
OCH(CH
3
)
2
33
CH
2
CH
2
CH
2
OH
H
CH(OH)CH
3
34
CH
2
CH
2
CH
2
OH
H
CH(OH)CH
2
CH
3
35
H
H
CH(OH)CH
3
36
H
H
(+/−) CH(OCH
3
)CH
3
37
CH
2
CH
2
CH
2
OCOCF
3
H
CH
2
SCH
2
CH
2
CH
3
38
CH
2
CH
2
CH
2
OH
H
CH
2
S(2-pyridyl)
39
CH
2
CH
2
CH
2
OH
H
CH
2
S(2

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