U.S. patent application number 10/566752 was filed with the patent office on 2006-09-07 for neuroprotective and anti-proliferative compounds.
Invention is credited to John W. Gillard, James B. Jaquith, Alain Laurent.
Application Number | 20060199835 10/566752 |
Document ID | / |
Family ID | 34135609 |
Filed Date | 2006-09-07 |
United States Patent
Application |
20060199835 |
Kind Code |
A1 |
Jaquith; James B. ; et
al. |
September 7, 2006 |
Neuroprotective and anti-proliferative compounds
Abstract
This invention features compounds of formula (I), (II) and
(III), which are useful in the treatment of proliferative disorders
characterized by loss of growth or cellular differentiation control
including, but not limited to, cancer and inflammation. Formulas
(I), (II), (III) have functional groups designated as A.sup.1,
A.sup.2, B.sup.1, B.sup.2, X.sup.1--X.sup.9 and R.sup.1--R.sup.8 as
defined further. ##STR1##
Inventors: |
Jaquith; James B.; (Quebec,
CA) ; Gillard; John W.; (Baie D'Urfe, CA) ;
Laurent; Alain; (Montreal, CA) |
Correspondence
Address: |
PHILIP SWAIN, PHD;C/O GOWLING LAFLEUR HENDERSON
1 PLACE VILLE MARIE,
37TH FLOOR
MONTREAL
QC
H3B 3P4
CA
|
Family ID: |
34135609 |
Appl. No.: |
10/566752 |
Filed: |
August 11, 2004 |
PCT Filed: |
August 11, 2004 |
PCT NO: |
PCT/CA04/01484 |
371 Date: |
February 1, 2006 |
Current U.S.
Class: |
514/300 ;
514/414; 546/113; 548/455 |
Current CPC
Class: |
C07D 403/08 20130101;
A61K 31/415 20130101; C07D 401/14 20130101; C07D 403/04 20130101;
A61P 25/02 20180101; A61P 29/00 20180101; A61P 43/00 20180101; C07D
471/04 20130101; A61K 31/47 20130101; A61K 31/435 20130101; C07D
403/14 20130101; A61P 35/00 20180101; A61P 25/28 20180101; A61K
31/40 20130101 |
Class at
Publication: |
514/300 ;
514/414; 546/113; 548/455 |
International
Class: |
A61K 31/4745 20060101
A61K031/4745; A61K 31/405 20060101 A61K031/405; C07D 403/14
20060101 C07D403/14; C07D 471/02 20060101 C07D471/02 |
Claims
1-30. (canceled)
1. A compound represented by the following formula: ##STR20## or a
pharmaceutically acceptable salt thereof wherein: X.sup.1--X.sup.3
are independently C or N; X.sup.4 is CH or N, wherein not more than
two of X.sup.1--X.sup.4 is N; X.sup.6--X.sup.8 are independently C
or N; X.sup.9 is CH or N, wherein not more than two of
X.sup.6--X.sup.9 is N; X.sup.5 is N, R.sup.5 is a lone pair, and
X.sup.10is CH, when the bond between X.sup.5 and X.sup.10 is a
double bond; or X.sup.5 is CH, R.sup.5 is H, and X.sup.10 is
CH.sub.2, when the bond between X.sup.5 and X.sup.10 is a single
bond; or X.sup.5 is C, R.sup.5 is defined below, and X.sup.10 is
CH, when the bond between X.sup.5 and X.sup.10 is a double bond;
R.sup.1--R.sup.3 and R.sup.6--R.sup.8 represent a lone pair or O
when each respective X.sup.1--X.sup.3 and X.sup.6--X.sup.8 is N; or
when X.sup.1--X.sup.3 or X.sup.6--X.sup.8 is C, each respective
R.sup.1--R.sup.3 and R.sup.6--R.sup.8 is independently selected
from the group consisting of: a) H, substituted or unsubstituted
C(1-8) alkyl, halogen, azido, cyano, nitro, or NR.sup.21R.sup.22,
wherein R.sup.21 represents H or C(1-8) alkyl, and R.sup.22
represents H, substituted or unsubstituted C(1-8) alkylcarbonyl,
substituted or unsubstituted arylcarbonyl, heterocycle, substituted
or unsubstituted heteroarylcarbonyl, substituted or unsubstituted
C(1-8) alkylaminocarbonyl, substituted or unsubstituted
arylaminocarbonyl; b) OR.sup.23, wherein R.sup.23 is H, substituted
or unsubstituted alkylcarbonyl, substituted or unsubstituted
arylcarbonyl; c) SR.sup.23, wherein R.sup.23 is defined as in b);
d) O(CH.sub.2).sub.j--R.sup.24, O(CH.sub.2).sub.j--O--R.sup.24, or
O(CH.sub.2).sub.j--S--R.sup.24, wherein j is an integer from 1 to
8, and R.sup.24 is selected from the group consisting of H,
substituted or unsubstituted C(1-8) alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl; e)
S(CH.sub.2).sub.jR.sup.24, S(CH.sub.2).sub.j--O--R.sup.24, or
S(CH.sub.2).sub.j--S--R.sup.24, wherein j and R.sup.24 are defined
as in d); f) C.ident.C--R.sup.25, C.ident.C--OR.sup.25, or
C.ident.C--CO.sub.2R.sup.25, wherein R.sup.25 is H, substituted or
unsubstituted C(1-8) alkyl, aryl, substituted aryl, heteroaryl, or
substituted heteroaryl; g) CH.dbd.CH--R.sup.25,
CH.dbd.CH--OR.sup.25, or CH.dbd.CH--CO.sub.2R.sup.25, having a
stereochemistry of E or Z, and R.sup.25 is defined as in f); h)
C.ident.C--NR.sup.25R.sup.26 or C.ident.CCONR.sup.25R.sup.26,
wherein R.sup.25 is defined as in f), and R.sup.26 is defined as
R.sup.25, and R.sup.25 and R.sup.26 are selected independently; i)
CH.dbd.CH--NR.sup.25R.sup.26 or CH.dbd.CHCONR.sup.25R.sup.26,
having a stereochemistry of E or Z, wherein R.sup.25 and R.sup.26
are independently defined as in h); j) (CH.sub.2).sub.kR.sup.25,
(CH.sub.2).sub.k--COOR.sup.25, or (CH.sub.2).sub.k--OR.sup.25,
wherein k is an integer from 2 to 6 and R.sup.25 is defined as in
f); k) (CH.sub.2).sub.kNR.sup.25R.sup.26,
(CH.sub.2).sub.kCONR.sup.25R.sup.26, wherein R.sup.25 and R.sup.26
are selected independently, and R.sup.25 and R.sup.26 are defined
as R.sup.25 in f); and l) CH.sub.2XR.sup.27, wherein X is O or S
and R.sup.27 is H, substituted or unsubstituted C(1-8) alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl; R.sup.4 is
selected from the group consisting of: m) H, substituted or
unsubstituted C(1-8) alkyl; and n) ##STR21## wherein X.dbd.O, S, or
NH, n=1 to 4; and wherein R.sup.51 is H; R.sup.52 and R.sup.53 are
independently chosen from the group consisting of H, substituted or
unsubstituted C(1-8)alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, or R.sup.51 and R.sup.52 are combined to
form a heteroalkyl, substituted heteroalkyl, heteroaryl, or
substituted heteroaryl ring system; R.sup.5 is selected from the
group consisting of: o) a lone pair when X.sup.5 is N; or when
X.sup.5 is C, R.sup.5 is selected from the group consisting of: p)
H, substituted and unsubstituted C(1-8) alkyl; and q) ##STR22##
wherein X.dbd.O, S, or NH, n=1 to 4; and wherein R.sup.51 is H;
R.sup.52 and R.sup.53 are independently chosen from the group
consisting of H, substituted or unsubstituted C(1-8) alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, or R.sup.51
and R.sup.52 are combined to form a heteroalkyl, substituted
heteroalkyl, heteroaryl, or substituted heteroaryl ring system; or
wherein when R.sup.1--R.sup.3 and R.sup.5--R.sup.8 are H, and
R.sup.4 is H or CH.sub.3, then at least one of X.sup.1--X.sup.9
represents a ring member other than carbon.
2. A compound, according to claim 1, in which X.sup.1--X.sup.3 are
independently C.
3. A compound, according to claim 1, in which X.sup.4 is CH.
4. A compound, according to claim 1, in which X.sup.6--X.sup.8 are
independently C.
5. A compound, according to claim 1, in which X.sup.9 is CH or
N.
6. A compound, according to claim 1, in which X.sup.5 is C,
X.sup.10 is CH and the bond between X.sup.5 and X.sup.10 is a
double bond.
7. A compound, according to claim 1, in Which X.sup.5 is N, R.sup.5
is a lone pair, X.sup.10 is CH and the bond between X.sup.5 and
X.sup.10 is a double bond.
8. A compound, according to claim 1, in which X.sup.5 is CH,
R.sup.5 is H, X.sup.10 is CH.sub.2 and the bond between X.sup.5 and
X.sup.10 is a single bond.
9. A compound having the following formula: ##STR23## wherein
X.sup.5 is C or N, and X.sup.1--X.sup.3, X.sup.4, X.sup.6--X.sup.8,
R.sup.1--R.sup.3, R.sup.4, R.sup.5 and R.sup.6--R.sup.8 are as
defined in claim 1.
10. A compound having the following formula: ##STR24## wherein
X.sup.1--X.sup.3, X.sup.4, X.sup.6--X.sup.8, R.sup.1--R.sup.3,
R.sup.4, R.sup.5 and R.sup.6--R.sup.8 are as defined in claim
1.
11. A compound having the following formula: ##STR25## wherein
X.sup.1--X.sup.3, X.sup.4, X.sup.6--X.sup.8, R.sup.1--R.sup.3,
R.sup.4, R.sup.5 and R.sup.6--R.sup.8 are as defined in claim
1.
12. A compound having the following formula: ##STR26## wherein
X.sup.1--X.sup.3, X.sup.4, X.sup.6--X.sup.8, R.sup.1--R.sup.3,
R.sup.4, R.sup.5 and R.sup.6--R.sup.8 are as defined in claim
1.
13. A compound, according to claim 1, in which when
X.sup.1--X.sup.3 or X.sup.6--X.sup.8 is C, each respective
R.sup.1--R.sup.3 and R.sup.6--R.sup.8 is independently selected
from the group consisting of: a) H, halogen; b) OR.sup.23, wherein
R.sup.23 is H, substituted or unsubstituted alkylcarbonyl,
substituted or unsubstituted arylcarbonyl; and d)
O(CH.sub.2).sub.j--R.sup.24, O(CH.sub.2).sub.j--O--R.sup.24, or
O(CH.sub.2).sub.j--S--R.sup.24, wherein j is an integer from 1 to
8, and R.sup.24 is selected from the group consisting of H,
substituted or unsubstituted C(1-8) alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl.
14. A compound, according to claim 1, in which R.sup.4 is selected
from the group consisting of: m) H, substituted or unsubstituted
C(1-8) alkyl; and n) ##STR27## wherein X.dbd.O, S, or NH, n=2; and
wherein R.sup.51 is H; R.sup.52 and R.sup.53 are independently
chosen from the group consisting of H, substituted or unsubstituted
C(1-8)alkyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, or R.sup.51 and R.sup.52 are combined to form a
heteroalkyl, substituted heteroalkyl, heteroaryl, or substituted
heteroaryl ring system.
15. A compound, according to claim 14, in which R.sup.4 is selected
from the group consisting of: m) H, substituted or unsubstituted
C(1-8) alkyl; and n) ##STR28## wherein X.dbd.S, n=2; and wherein
R.sup.51 is H; R.sup.52 and R.sup.53 are both H, or R.sup.51 and
R.sup.52 are combined to form a heteroaryl ring system.
16. A compound, according to claim 15, in which R.sup.4 is selected
from the group consisting of: H, methyl,
CH.sub.2CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2N.sub.3,
CH.sub.2CH.sub.2CH.sub.2SC(.dbd.NH)NH.sub.2 and ##STR29##
17. A compound, according to claim 1, in which X.sup.5 is N and
R.sup.5 is a lone pair.
18. A compound, according to claim 1, in which X.sup.5 is C or CH,
and R.sup.5 is selected from the group consisting of: p) H,
substituted and unsubstituted C(1-8) alkyl; and q) ##STR30##
wherein X.dbd.S, n=2; and wherein R.sup.51 is H; R.sup.52 and
R.sup.53 are independently chosen from the group consisting of H,
substituted or unsubstituted C(1-8) alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, or R.sup.51 and R.sup.52 are
combined to form a heteroalkyl, substituted heteroalkyl,
heteroaryl, or substituted heteroaryl ring system.
19. A compound, according to claim 18, in which X.sup.5 is C or CH,
and R.sup.5 is selected from the group consisting of H, methyl,
CH.sub.2CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2CH.sub.2SC(.dbd.NH)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.2N.sub.3, CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
and ##STR31##
20. A compound, according to the following formula ##STR32##
selected from the group consisting of: TABLE-US-00004 Bond between
Cpd. X.sup.5/X.sup.10 R.sup.3 R.sup.50 R.sup.7 X.sup.5/R.sup.5
X.sup.9 X.sup.10 121 Double H --OH H CH CH CH; 124 Double BnO --OH
H CH CH CH; 125 Double H --OH H CMe CH CH; 126 Double H --OH BnO CH
CH CH; 127 Double H --OH H CH CH CMe; 128 Double H --OH H N CH CH;
129 Double BnO --OH H CMe CH CH; 130 Double H --OH H CH N CH; 131
Double BnO --OH H CH CH CMe; 132 Double H --OH F CH CH CH; 133
Double H --N(CH.sub.3).sub.2 H CH CH CH; 136 Double BnO
--N(CH.sub.3).sub.2 H CH CH CH; 137 Double H --N(CH.sub.3).sub.2 H
CMe CH CH; 138 Double H --N(CH.sub.3).sub.2 BnO CH CH CH; 139
Double H --N(CH.sub.3).sub.2 H CH CH CMe; 140 Double H
--N(CH.sub.3).sub.2 H N CH CH; 141 Double BnO --N(CH.sub.3).sub.2 H
CMe CH CH; 142 Double H --N(CH.sub.3).sub.2 H CH N CH; 143 Double H
--SC(.dbd.NH)NH.sub.2 H CH CH CH; 146 Double H
--SC(.dbd.NH)NH.sub.2 H CMe CH CH; 147 Double H
--SC(.dbd.NH)NH.sub.2 BnO CH CH CH; 148 Double BnO
--SC(.dbd.NH)NH.sub.2 H CH CH CH; 149 Double BnO
--SC(.dbd.NH)NH.sub.2 H CH CMe CH; 150 Double BnO
--SC(.dbd.NH)NH.sub.2 H CH CH CMe; 151 Double H
--SC(.dbd.NH)NH.sub.2 H CH CH CMe; 152 Double H
--SC(.dbd.NH)NH.sub.2 H CH N CH; 153 Double MeO
--SC(.dbd.NH)NH.sub.2 H CH CH CH; 154 Double F
--SC(.dbd.NH)NH.sub.2 H CH CH CH; 155 Double H
--SC(.dbd.NH)NH.sub.2 F CH CH CH; 156 Double H ##STR33## H CH CH
CH; 159 Single H --SC(.dbd.NH)NH.sub.2 H CH.sub.2 CH CH.sub.2; 160
Double OCH.sub.2S --SC(.dbd.NH)NH.sub.2 H CH CH CH; Ph 161 Double H
--N.sub.3 H CH CH CH; and 162 Double H --NH.sub.2 H CH CH CH.
21. A compound according to the following formula: ##STR34##
selected from the group consisting of: TABLE-US-00005 Example
R.sup.3 R.sup.50 R.sup.7 R.sup.4 163 H OH H H; 164 H OH H Me; 165
BnO OH H H; 166 H SC(.dbd.NH)NH.sub.2 H H; 167 H
SC(.dbd.NH)NH.sub.2 H Me; 168 BnO SC(.dbd.NH)NH.sub.2 H Me; 169 H
N(CH.sub.3).sub.2 H Me; 170 H ##STR35## H Me; 171 H N.sub.3 H Me;
and 172 H NH.sub.2 H Me.
22. A composition comprising a compound, according to claim 1, in
combination with carrier.
23. The composition, according to claim 22, further including a
chemotherapeutic agent.
24. The composition, according to claim 22, further including a
cytokine.
25. The composition, according to claim 22, further including
anti-sense oligonucleotides.
26. A method of treating an inflammatory disorder, the method
comprising: administering to a subject in need thereof an effective
amount of a compound or a composition, according to claim 1 or 22,
so as to treat the disorder.
27. A method of treating cancer, the method comprising:
administering to a subject in need thereof an effective amount of a
compound or a composition, according to claim 1 or 22, so as to
treat the cancer.
28. A method of treating a cell proliferative disorder, the method
comprising: administering to a subject in need thereof an effective
amount of a compound or a composition, according to claim 1 or 22,
so as to treat the disorder.
29. A method of treating cancer, the method comprising:
administering to a subject in need thereof an effective amount of a
compound or a composition, according to claim 1 or 22, in
combination with another chemotherapeutic agent.
30. Use of a compound or a composition, according to claim 1 or 22,
so as to induce apoptosis in Jurkat cells.
31. Use of a compound or a composition, according to claim 1 or 22,
so as to induce apoptosis in cancer cell lines.
32. The use, according to claim 31, in which the cancer cell lines
are prostate cancer and breast cancer cell lines
33. A method of treatment or prevention of a condition resulting
from loss of growth and cellular differentiation control, the
method comprising: administration to a subject in need thereof an
effective amount of a compound or a composition, according to claim
1 or 22, so as to treat or prevent the condition.
Description
[0001] This application is a continuation-in-part of and claims
priority to U.S. patent application Ser. No. 10/276,803 (filed May
18, 2001), the entirety of which is herein incorporated by
reference. U.S. patent application Ser. No. 10/276,803 is the
National Phase application of PCT/CA01/00718 (filed May 18, 2001),
the entirety of which is herein incorporated by reference. This
application claims priority to Canadian Patent Application Serial
No. 2,308,994 (Filed May 19, 2000), the entirety of which is herein
incorporated by reference.
FIELD OF THE INVENTION
[0002] This invention features compounds of formula I, which are
useful in the treatment and prevention of cancer and inflammation
by inducing apoptosis in proliferating cells.
BACKGROUND OF THE INVENTION
[0003] Cancer is one of the leading causes of death in North
America. Cancer cells may be loosely characterized as rapidly
multiplying and invasive cells which grow and migrate through out
the body. Localized areas of cellular proliferation are referred to
as tumors which may interrupt regular organ function, resulting in
organ disfunction and death. These cells have overcome internal
death signaling mechanisms which would normally regulate their
population, proliferation, and mobility. Alternatively, these cells
upregulate various survival mechanisms which prevent the cell from
initiating apoptosis. In several cases, the cytotoxic properties of
the indolocarbazoles such as staurosporine, UNC 01, Rebeccamycin
and NB 506, have been exploited to affect a therapeutic use in
cancer.
[0004] Various cancers and cancer cell lines, including colon,
lung, and breast, display elevated levels of the Inhibitor of
Apoptosis Proteins (IAPs), including HIAP1,2 and XIAP, as either
mRNA and/or protein (U.S. Pat. No. 5,919,912). The down-regulation
of the IAPs in cancer cells can effectively shift the
chemotherapeutic dose response required to kill such cancer cells,
in the case of HAIP1, or to kill cancer cells outright, in the case
of XIAP. Compounds that down-regulate the expression of these genes
and/or proteins would therefore be useful in treating cancers.
[0005] Diseases such as MS and ALS are characterized by progressive
neuronal damage and cell loss in the central and peripheral nervous
systems (CNS and PNS respectively). Pathology of MS is believed to
involve autoimmune recognition of self-antigens by autoreactive T
lymphocytes (Antel J. J. Neuroimmunol. (1999), 98, 45). Control
over the development and relative populations of T-lymphocytes
proceeds via apoptotic cell death. Aberant autoreactive T
lymphocyte populations may lead to neuronal demyelinization and
disease progression. Recently, it has been observed that these
"potentially pathogenic autoreactive T-lymphocyctes" escape regular
apoptotic control by the upregulation of the IAPs (Shareif M. K.
et. al., J. Neuroimmunology (2002), 129, 159; 224). Therefore,
therapies which induce apoptosis of autoreactive T-lymphocyctes
represent novel therapies for inflammation and autoimmune diseases
such as MS.
[0006] Stimulation of the tumor necrosis factor (TNF) receptor
family of proteins, such as CD95 (Fas/APO-1), TNFR1, and DR5, with
their respective ligands Fas, TNF-.alpha., and TRAIL, result in the
initiation of apoptosis via caspase-8 mediated death signal.
Defects in this signaling mechanism may lead to cellular
populations which overcome normal apoptotic signaling leading to
uncontrolled cellular proliferation as seen in various inflammatory
diseases, in aberrant autoreactive T-lymphocyte populations
implicated in MS, and in tumor formation and cancer. The
bis-indolemaleimides Bis VIII and Bis IX are known PKC inhibitors
(Davis, P. D., et al., J. Med. Chem. (1992), 35, 994). These
compounds have recently been shown to sensitize various Fas,
TNF-.alpha., and/or TRAIL resistant cancer cell lines to TNF
receptor mediated apoptosis (Zhou, T., et al., Nature Medicine,
(1999), 5, 42). It is suggested that this sensitization is
independent of PKC activity. Compounds which augment apoptosis
mediated by TNF receptor family signaling will be useful in the
treatment of uncontrolled cellular proliferation.
[0007] The applicants have recently reported the synthesis of a
series of 3-(indol-1-yl)-4-(indol-3-yl)-pyrrole-2,5-diones and
3-(benzimidazol-1-yl)-4-(indol-3-yl)-pyrrole-2,5-diones,
represented by Formula I of PCT/CA01/00718. These compounds were
prepared using a novel cyclization reaction, for the preparation of
neuroprotective and anti-cancer compounds. ##STR2##
[0008] The applicant herein discloses the preparation and use of a
series of 3-(indol-1-yl)-4-(indol-3-yl)-pyrrole-2,5-diones and
3-(benzimidazol-1-yl)-4-(indol-3-yl)-pyrrole-2,5-diones which have
been functionalized at R.sup.4 and/or R.sup.5 with alkylthioamidino
related moieties (formula I). Additionally,
3-(indolin-1-yl)-4-(indol-3-yl)-pyrrole-2,5-diones, represented by
formula II, are disclosed.
[0009] Compounds of formula I and II have been shown by the
applicant to induce apoptosis either alone or synergistically with
anti-Fas to incude apoptosis in several cancer cells including
jurkats. Jurkats are often used as a model of autoreactive
T-lymphocytes and the ability to kill jurkats may often be
correlated to efficacy in models of autoimmune disease. These
compounds are useful in the treatment and prevention of cancer and
inflammation.
[0010] 3-(1-Indol-1-yl)-4-(1-methylindol-3-yl)-pyrrole-2,5-dione
was first reported by Davis et al. (J. Med. Chem., 1992, 35, 177)
as an inhibitor of PKC. This compound was prepared using a
different chemistry than that of the applicant. No other reports or
uses of these compounds have been disclosed.
[0011] The disclosed compounds resemble but display distinctly
different biological profiles to the indolocarbazole alkaloids
Staurosporine and K252a. Various derivatives of these natural
products have been described for the treatment of neurodegenerative
disorders (U.S. Pat. No. 6,013,646 WO96/31515,WO 97/46565 and
WO97/49406). Other indolocarbazole derivatives are disclosed by
Glicksman, M. A. et al. (WO 95 07911), Lewis, M. E. (WO 94 02488),
Lewis, M. E. et al. (U.S. Pat. No. 5,756,494, U.S. Pat. No.
5,741,808, and U.S. Pat. No. 5,621,101). Indolocarbazole
derivatives have also been reported for use in treatment of cancer
(EP 0 323 171, EP 0 643 966, U.S. Pat. No. 4,923,986, U.S. Pat. No.
4,877,776, WO 94/27982, WO99/47522), as antimicrobial agents
(Prudhomme et al, J. Antibiotics, 1994, 47, 792) and in the
treatment of hypertension (Hachisu et al. Life Sciences 1989, 44,
1351).
[0012] A variety of synthetic procedures have been reported in the
literature for the preparation of bis(indolyl)pyrrole-2,5-diones
and indolocarbazoles. See, for example, Bit et al., J. Med. Chem.,
1993, 63, 21; Bergman et al., Tetrahedron Lett., 1987, 28, 4441;
Davis et al., Tetrahedron Lett., 1990, 31, 2353, 5201; Faul, M. M.
et al., Tetrahedron Lett., 1999, 40, 1109; Faul M. M. et al. U.S.
Pat. No. 5,859,261, U.S. Pat. No. 5,919,946, and U.S. Pat. No.
6,037,475. For synthetic studies see Wood, J. L. et al. J. Am.
Chem. Soc. 1997, 119, 9641; and Danishefsky, S. et al. J. Am. Chem.
Soc. 1996, 118, 2825.
SUMMARY OF THE INVENTION
[0013] The present invention provides novel compounds of formula I
and II (defined as subcategories of a broader group of compounds of
formula III). Compounds disclosed herein are useful in the
prevention and treatment of disorders and physiological conditions
characterized by loss of growth and cellular differentiation
control, as exemplified in cancer and inflammation.
[0014] The invention also relates to a general synthetic route,
permitting preparation of compounds of formula I and If which are
distinct from the indolocarbazole class of compounds and their
synthetic precursors, which represent
3-(indol-1-yl)-4-(indol-3-yl)-pyrrole-2,5-diones and
3-(benzimidazol-1-yl)-4-(indol-3-yl)-pyrrole-2,5-diones,
represented by formula I, and
3-(indolin-1-yl)-4-(indol-3-yl)-pyrrole-2,5-diones, represented by
formula II.
[0015] Also included are inventive methods for the preparation of
the compounds disclosed herein.
[0016] The present invention are compounds of formula I and II:
##STR3##
[0017] These are subcategories of a broader group of compounds of
the formula III: ##STR4##
[0018] Formulas I, II and III have functional groups designated as
A.sup.1, A.sup.2, B.sup.1, B.sup.2, X.sup.1--X.sup.9 and
R.sup.1--R.sup.8 as defined further herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] The invention is now described with reference to the
accompanying drawings described below.
[0020] FIG. 1 depicts the killing of DU145 prostate cancer cells
with compound 136 (described in Example 136). A survival curve is
shown for DU145 after seven days of treatment with the compound at
varying concentrations.
[0021] FIG. 2 depicts the killing of Jurkats with compounds 167 and
168 (described in Examples 167 and 168) with and without anti-Fas
over 19 hours. Survival is plotted against concentration.
DETAILED DESCRIPTION
Ring-Substitution and Structural Derivatives of Compounds of
Formula I, II and III
[0022] Disclosed herein are pharmaceutically active
ring-substitution and structural derivatives represented by formula
I, II and III; ##STR5## and pharmaceutically acceptable salts
thereof wherein:
[0023] X.sup.1--X.sup.3 are independently C or N;
[0024] X.sup.4 is CH or N, wherein not more than two of
X.sup.1--X.sup.4 is N;
[0025] X.sup.6--X.sup.8 are independently C or N;
[0026] X.sup.9 is CH or N, wherein not more than two of
X.sup.6--X.sup.9 is N;
[0027] R.sup.1--R.sup.3 and R.sup.6--R.sup.8 represent a lone pair
or O when each respective X.sup.1--X.sup.3 and X.sup.6--X.sup.8 is
N; and
[0028] when X.sup.1--X.sup.3 or X.sup.6--X.sup.8 is C, each
respective R.sup.1--R.sup.3 and R.sup.6--R.sup.8 is independently
selected from the group consisting of: [0029] a) H, substituted or
unsubstituted C(1-8) alkyl, halogen, azido, cyano, nitro, or
NR.sup.21R.sup.22, wherein R.sup.21 represents H or C(1-8) alkyl,
and R.sup.22 represents H, substituted or unsubstituted C(1-8)
alkylcarbonyl, substituted or unsubstituted arylcarbonyl,
heterocycle, substituted or unsubstituted heteroarylcarbonyl,
substituted or unsubstituted C(1-8) alkylaminocarbonyl, substituted
or unsubstituted arylaminocarbonyl; [0030] b) OR.sup.23, wherein
R.sup.23 is H, substituted or unsubstituted alkylcarbonyl,
substituted or unsubstituted arylcarbonyl; [0031] c) SR.sup.23,
wherein R.sup.23 is defined as in b); [0032] d)
O(CH.sub.2).sub.j--R.sup.24, O(CH.sub.2).sub.j--O--R.sup.24, or
O(CH.sub.2).sub.j--S--R.sup.24, wherein j is an integer from 1 to
8, and R.sup.24 is selected from the group consisting of H,
substituted or unsubstituted C(1-8) alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl; [0033]
e) S(CH.sub.2).sub.jR.sup.24, S(CH.sub.2).sub.j--O--R.sup.24, or
S(CH.sub.2).sub.j--S--R.sup.24, wherein j and R.sup.24 are defined
as in d); [0034] f) C.ident.C--R.sup.25, C.ident.C--OR.sup.25, or
C.ident.C--CO.sub.2R.sup.25, wherein R.sup.25 is H, substituted or
unsubstituted C(1-8) alkyl, aryl, substituted aryl, heteroaryl, or
substituted heteroaryl; [0035] g) CH.dbd.CH--R.sup.25,
CH.dbd.CH--OR.sup.25, or CH.dbd.CH--CO.sub.2R.sup.25, having a
stereochemistry of E or Z, and R.sup.25 is defined as in f); [0036]
h) C.dbd.C--NR.sup.26R.sup.26 or C.ident.CCONR.sup.25R.sup.26,
wherein R.sup.25 is defined as in f), and R.sup.26 is defined as
R.sup.25, and R.sup.25 and R.sup.26 are selected independently,
[0037] i) CH.dbd.CH--NR.sup.25R.sup.26 or
CH.dbd.CHCONR.sup.25R.sup.26, having a stereochemistry of E or Z,
wherein R.sup.25 and R.sup.26 are independently defined as in h);
[0038] j) (CH.sub.2).sub.kR.sup.25, (CH.sub.2).sub.k--COOR.sup.25,
or (CH.sub.2).sub.k--OR.sup.25, wherein k is an integer from 2 to 6
and R.sup.25 is defined as in f); [0039] k)
(CH.sub.2).sub.kNR25R.sup.26, (CH.sub.2).sub.kCONR.sup.25R.sup.26,
wherein R.sup.25 and R.sup.26 are selected independently, and
R.sup.25 and R.sup.26 are defined as R.sup.25 in f); [0040] l)
CH.sub.2XR.sup.27, wherein X is O or S and R.sup.27 is H,
substituted or unsubstituted C(1-8) alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl;
[0041] R.sup.4 is selected from the group consisting of: [0042] m)
H, substituted or unsubstituted C(1-8) alkyl [0043] n) ##STR6##
wherein X.dbd.O, S, or NH, n=1 to 4, and R.sup.51 is H, R.sup.52
and R.sup.53 are independently chosen from the group consisting of
H, substituted or unsubstituted C(1-8)alkyl, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, or R.sup.51 and R.sup.52
are combined to form a heteroalkyl, substituted heteroalkyl,
heteroaryl, or substituted heteroaryl ring system;
[0044] R.sup.5 is selected from the group consisting of: [0045] o)
a lone pair when X.sup.5 is N; when X.sup.5 is C, R.sup.5 is
selected from the group consisting of: [0046] p) H, substituted and
unsubstituted C(1-8) alkyl:); or [0047] q) ##STR7## wherein
X.dbd.O, S, or NH, n=1 to 4 and R.sup.51 is H, R.sup.52 and
R.sup.53 are independently chosen from the group consisting of H,
substituted or unsusbstituted C(1-8) alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, or R.sup.51 and R.sup.52 are
combined to form a heteroalkyl, substituted heteroalkyl,
heteroaryl, or substituted heteroaryl ring system; or
[0048] wherein in formula I, when A.sup.1 and A.sup.2, and B.sup.1
and B.sup.2 , respectively combine to form oxygen, R.sup.1--R.sup.3
and R.sup.5--R.sup.8 are H, and R.sup.4 is H or CH.sub.3, at least
one of X.sup.1--X.sup.9 represents a ring member other than
carbon.
[0049] Notably, within the structure of formula I or II, up to two
of the outer ring members of either indole/indoline benzene rings,
at positions X.sup.1 to X.sup.4 and X.sup.6 to X.sup.9 may be N.
Thus, each of the two indole/indoline benzene rings may have zero,
one or two N present at any of the outer four positions.
[0050] The generic group is of the formula III: ##STR8## or more
particularily ##STR9## and pharmaceutically acceptable salts
thereof wherein:
[0051] X.sup.1--X.sup.3 are independently C or N;
[0052] X.sup.4 is CH or N, wherein not more than two of
X.sup.1--X.sup.4 is N;
[0053] when X.sup.5 is N, R.sup.5 is a lone pair, X.sup.10 is CH
and the bond between X.sup.5 and X.sup.10 is a double bond (as in a
benzimidazole ring system);
[0054] when X.sup.5 is CH, R.sup.5 is H, X.sup.10 is CH.sub.2 and
the bond between X.sup.5 and X.sup.10 is a single bond (as in an
indoline ring system);
[0055] when X.sup.5 is C, R.sup.5 may be defined as below, X.sup.10
is CH and the bond between X.sup.5 and X.sup.10 is a double bond
(as in an indole ring system);
[0056] X.sup.6--X.sup.8 are independently C or N.;
[0057] X.sup.9 is CH or N, wherein not more than two of
X.sup.6--X.sup.9 is N.;
[0058] R.sup.1--R.sup.3 and R.sup.6--R.sup.8 represent a lone pair
or O when each respective X.sup.1--X.sup.3 and X.sup.6--X.sup.8 is
N; and the balance of the definitions is as above.
Pharmaceutically Acceptable Salts
[0059] Pharmaceutically acceptable salts of formula I, II and III
may be any salt such as an acid salt, a basic salt or a neutral
salt. For example, a salt may be prepared by the direct protonation
of a nitrogen found at any of positions X.sup.1--X.sup.9 in
formulas I, II and III, with a pharmaceutically acceptable acid; or
by the protonation of a basic nitrogen found at any of positions
R.sup.1--R.sup.9 of formula I, I and III, with a pharmaceutically
acceptable acid. These basic nitrogens are exemplified by primary,
secondary, or tertiary amines, and heteroaryl moieties containing
nitrogen, exemplified by pyridyl and quinolinyl ring systems.
[0060] Pharmaceutically acceptable salts of formula I, II and III
may be prepared by the treatment of an acidic moiety found in a
position such as R.sup.1--R.sup.9 of formula I, II to III, with a
pharmaceutically acceptable base. These acidic moieties are
exemplified by hydrochloric, methanesulfonic, carboxylic, sulfonic,
and boronic acids.
[0061] Pharmaceutically acceptable acid and basic salts are
exemplified herein.
Substitutent Definitions
[0062] In the definitions of the groups of Formula I, II and III,
C(1-8) alkyl means a straight-chain or branched alkyl group having
1 to 8 carbon atoms, such as methyl, ethyl, propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso-amyl,
neopentyl, 1-ethylpropyl, hexyl, and octyl. The C(1-8) alkyl moiety
of C(1-8) alkoxy, C(1-8) alkylsulfonyl, C(1-8) alkoxylcarbonyl,
C(1-8) alkylaminocarbonyl has the same meaning as C(1-8) alkyl
defined above. The C(1-8) alkylcarbonyl moiety means a
straight-chain or branched alkanoyl group having 1 to 6 carbon
atoms, such as acetyl, propanoyl, butyryl, valeryl, pivaloyl and
hexanoyl, and arylcarbonyl group described below, or a
heteroarylcarbonyl group described below. The aryl moiety of the
aryl, the arylcarbonyl and arylaminocarbonyl groups means a group
having 6 to 16 carbon atoms such as phenyl, biphenyl, naphthyl, or
pyrenyl. The heteroaryl moiety of the heteroaryl,
heteroarylcarbonyl, and heteroarylaminocarbonyl groups contain at
least one hetero atom from O, N, and S, such as, but not limited to
pyridyl, pyrimidyl, pyrroleyl, furyl, benzofuryl, thienyl,
benzothienyl, imidazolyl, triazolyl, quinolyl, iso-quinolyl,
benzoimidazolyl, thiazolyl, benzothiazolyl, oxazolyl, and indolyl.
The aralkyl moiety of the aralkyl and the aralkyloxy groups having
7 to 15 carbon atoms, such as benzyl, phenethyl, benzhydryl, and
naphthylmethyl. The heteroaralkyl moiety of the heteroaralkyl and
the heteroaralkyloxy groups having 7 to 15 carbon such as
pyridylmethyl, quinolinylmethyl, and iso-quinolinylmethyl. The
substituted C(1-8) alkyl group has 1 to 3
independently-substitutuents, such as but not limited to hydroxyl,
C(1-8) alkoxy, carboxyl, C(1-8) alkylcarbonyl, nitro, amino, mono-
or di-lower alkylamino, dioxolane, dioxane, dithiolane, and
dithione. The C(1-8) alkyl moiety of the substituted C(1-8) alkyl,
and the C(1-8) alkyl moeity of the C(1-8) alkoxy, the C(1-8)
alkoxycarbonyl, and the mono- and di-lower alkylamino in the
substituents of the substituted C(1-8) alkyl group have the same
meaning as C(1 -8) alkyl defined above. The substituted aryl, the
substituted heteroaryl, the substituted aralkyl, and the
substituted heteroaralkyl groups each has 1 to 5
independently-selected substituents, such as but not limited to
C(1-8) alkyl, hydroxy, C(1-8) alkoxy, carboxy, C(1-8)
alkoxycarbonyl, nitro, amino, mono or di-C(1-8) alkylamino, azido,
and halogen. The C(1-8) alkyl moiety of the C(1-8) alkyl, the
C(1-8) alkoxy, the C(1-8) alkylamino, and the mono- and di-C(1-8)
alkylamino groups amoung the susbtituents has the same meaning as
C(1-8) alkyl defined above. The heterocyclic group formed with a
nitrogen atom includes rings such as, but not limited to, pyrrolyl,
piperidinyl, piperidino, morpholinyl, morpholino, thiomorpholino,
N-methylpiperazinyl, indolyl, and isoindolyl. The cycloalkyl moeity
means a cycloalkyl group of the indicated number of carbon atoms,
containing one or more rings anywhere in the structure, such as
cycloalkyl groups include cyclopropyl, cyclopropylmethyl,
cyclobutyl, cyclopentyl, cyclohexyl, 2-norbornyl, 1-adamantyl and
the like. The fluoroalkyl moiety means a lower fluoroalkyl group in
which one or more hydrogens of the corresponding C(1-8) alkyl
group, as defined above, is replaced by a fluorine atom, such as
CH.sub.2F, CHF.sub.2, CF.sub.3, CH.sub.2CF.sub.3, and
CH.sub.2CH.sub.2CF.sub.3.
[0063] Some of the compounds described herein contain one or more
chiral centres and may thus give rise to diastereomers and optical
isomers. The present invention is meant to comprehend such
diastereomers as well as their racemic, resolved and
enantiomerically pure forms, and pharmaceutically acceptable salts
thereof.
[0064] Some of the compounds described herein contain olefinic
double bonds, and unless specified otherwise, are meant to include
both E and Z isomers.
[0065] As used herein, the following terms denote functional
groups: Me=methyl, Bn=benzyl, Ph=phenyl, .sup.tBu=t-butyl,
Ac=acetyl, Ts=tosyl, pyr=pyruvate, Phth=phthalate, Et=ethyl,
Boc=tert-butoxycarbonyl.
[0066] As used herein the following terms denote the following
reagents: NaH=sodium hydride; DMF=dimethylformamide;
TBS=tert-butyldimethylsilyl; KO.sup.tBu=potassium tert-butoxide;
THF=tetrahydrofuran; Ms.sub.2O=methanesulfonic anhydride;
Ms=methanesulfonyl; TsOH=p-tolenesulfonic acid,
Ph.sub.3P=triphenylphosphine; HCl=hydrochloric acid;
DIBAL=diisobutylaluminum hydride; pyr=pyridine.
[0067] The term "subject" or "patient" as used herein refers to any
mammal including humans, primates, horses, cows, pigs, sheep,
goats, dogs, cats and rodents.
[0068] The pharmaceutical compositions of the invention are
administered to subjects so as to deliver the compound of formula
I, II and III in an effective amount. An effective amount means
that amount necessary to delay the onset of, inhibit the
progression of, halt altogether the onset or progression of, or
diagnose the particular condition or symptoms of the particular
condition being treated. In general, an effective amount for
treating a inflammatory disorder is that amount necessary to affect
any symptom or indicator of the condition, in situ. In general, an
effective amount for treating cancer will be that amount necessary
to favorably affect mammalian cancer cell proliferation in situ.
When administered to a subject, effective amounts will depend, of
course, on the particular condition being treated; the severity of
the condition; individual patient parameters including age,
physical condition, size and weight; concurrent treatment;
frequency of treatment; and the mode of administration. These
factors are well known to those of ordinary skill in the art and
can be addressed with no more than routine experimentation.
Advantageously, a maximum dose is used, that is, the highest safe
dose according to sound medical judgment.
[0069] A variety of administration routes are available. The
particular mode selected will depend, of course, upon the
particular condition being treated, the particular compound
selected, the severity of the condition being treated, and the
dosage required for therapeutic efficacy. The methods of this
invention, generally speaking, may be practiced using any mode of
administration that is medically acceptable, meaning any mode that
produces effective levels of the compounds of any of formulas I, II
and III without causing clinically unacceptable adverse effects.
Such modes of administration include oral, rectal, sublingual,
topical, nasal, transdermal, intradermal or parenteral routes. The
term "parenteral" includes subcutaneous, intravenous,
intramuscular, or infusion. Oral routes are advantageous because of
the ease with which a subject can ingest an oral dosage form.
[0070] Dosage levels may be adjusted appropriately to achieve
desired levels of a compound of formula I, II and III, either
locally or systemically. Generally, a daily oral dose of a compound
of formula I, II and III will be from about 0.01 mg/kg per day to
1000 mg/kg per day. Multiple daily doses would be effective as
tolerated by the subject. In the event that the response in a
subject is insufficient at such doses, even higher doses (or
effective higher doses by a different, more localized delivery
route) may be employed to the extent that a subject's tolerance
permits.
[0071] The compositions containing compounds according to the
invention may conveniently be presented in unit dosage form and may
be prepared by any of the methods well known in the art of
pharmacy. All methods include the step of bringing the compounds of
the invention into association with a carrier that constitutes one
or more accessory ingredients. In general, the compositions are
prepared by uniformly and intimately bringing the compounds into
association with a liquid carrier, a finely divided solid carrier,
or both, and then, if necessary, shaping the product.
[0072] Compositions suitable for oral administration may be
presented as discrete units such as capsules, cachets, tablets, or
lozenges, each containing a predetermined amount of the compound of
formula I, II and III. Other compositions include suspensions in
aqueous liquors or non-aqueous liquids such as a syrup, an elixir,
or an emulsion.
[0073] Other delivery systems can include time-release, delayed
release or sustained release delivery systems. Such systems can
avoid repeated administrations of the compounds of formula I, II
and III, thereby increasing convenience to the subject and the
physician. Many types of release delivery systems are available and
known to those of ordinary skill in the art. They include polymer
based systems such as polylactic and polyglycolic acid,
polyanhydrides and polycaprolactone; nonpolymer systems that are
lipids including sterols such as cholesterol, cholesterol esters
and fatty acids or neutral fats such as mono-, di- and
triglycerides; hydrogel release systems; silastic systems; peptide
based systems; wax coatings, compressed tablets using conventional
binders and excipients, partially fused implants and the like. In
addition, a pump-based hardware delivery system can be used, some
of which are adapted for implantation.
[0074] A long-term sustained release implant also may be used.
"Long-term" release, as used herein, means that the implant is
constructed and arranged to deliver therapeutic levels of the
active ingredient for at least 30 days, and preferably 60 days.
Long-term sustained release implants are well known to those of
ordinary skill in the art and include some of the release systems
described above. Such implants can be particularly useful in
treating solid tumors by placing the implant near or directly
within the tumor, thereby affecting localized, high-doses of the
compounds of the invention.
[0075] When administered, the compositions according to the
invention may contain other pharmaceutically acceptable components.
Such compositions may contain salts, buffering agents,
preservatives, compatible carriers, and optionally other
therapeutic ingredients. When used in medicine the salts should be
pharmaceutically acceptable, but non-pharmaceutically acceptable
salts may be used in synthetic reactions to prepare
pharmaceutically acceptable salts therefrom, and are not excluded
from the scope of the invention. Such salts include, but are not
limited to, those prepared from the following acids: hydrochloric,
hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic,
salicylic, p-toluenesulfonic, tartaric, citric, methane sulfonic,
formic, malonic, succinic, naphthalene-2-sulfonic, and benzene
sulfonic. Also, pharmaceutically acceptable salts can be prepared
as alkaline metal or alkaline earth salts, such as sodium,
potassium or calcium salts.
[0076] Suitable buffering agents include: acetic acid and salts
thereof (1-2% W/V); citric acid and salts thereof (1-3% W/V); and
phosphoric acid and salts thereof (0.8-2% W/V), as well as others
known in the art. Suitable preservatives include benzalkonium
chloride (0.003-0.03% W/V); chlorobutanol (0.3-0.9% W/V); parabens
(0.01-0.25% W/V) and thimerosal (0.004-0.02% W/V), as well as
others known in the art. Suitable carriers are pharmaceutically
acceptable carriers. The term pharmaceutically acceptable carrier
means one or more compatible solid or liquid filler, dilutents or
encapsulating substances that are suitable for administration to a
human or other mammal. The term "carrier" denotes an organic or
inorganic ingredient, natural or synthetic, with which the active
ingredient is combined to facilitate the application. The
components of the pharmaceutically acceptable carrier are capable
of being commingled with the molecules of the compounds of formula
I, II and III of the present invention, and with each other, in a
manner such that there is no interaction which would substantially
impair the desired pharmaceutical efficacy. Carrier formulations
suitable for oral, subcutaneous, intravenous, and intramuscular
administration etc., are those known in the art.
[0077] The compounds of the invention may be delivered with other
therapeutic agents. The invention additionally includes
co-administration of any of the compounds of formula I, II and III
with other compounds known to be useful in treating inflammatory
diseases and cancer.
[0078] Compounds of formulas I, II and III have been shown to
induce apoptosis in several cancer cell lines and in jurkat cells,
which may be considered a serogat for auto-reactive
T-lymphocytes.
[0079] In the case of inflammatory diseases and cancer, the
compound represented by formula I, II and III are either delivered
separately as a mono-therapy, or in combination with other
chemotherapeutic agents,each administered at effective time
intervals, during an overlapping period of treatment in order to
augment the known effects of chemotherapeutic agent such as, but
not limited to, 5-fluorouracil (5-FU), dideoxyinosine, cisplatin,
etoposide, vincristine, or taxol.
[0080] In the case of cancer, the compounds would be delivered
separately or in the form of anti-cancer cocktails. An anti-cancer
cocktail is a mixture of any one of the compounds having formula I,
II or III with another anti-cancer agent such as an anti-cancer
drug, a cytokine, and/or supplementary potentiating agent(s). The
use of cocktails in the treatment of cancer is routine. In this
embodiment, a common administration vehicle (e.g., pill, tablet,
implant, injectable solution, etc.) could contain both a compound
of formula I, II or III and the anti-cancer drug and/or
supplementary potentiating agent. Thus, cocktails comprising of
formula I, II and III compounds as well as other compounds are
within the scope of the invention. Compounds having anti-neoplastic
properties include, but are not limited to: Antineoplastic:
Acivicin; Aclarubicin; Acodazole Hydrochloride; Acronine;
Adozelesin; Aldesleulin; 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; Dezaguanin; 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; Ethiodized Oil I 131; Etoposide;
Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine;
Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil;
Flurocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine;
Gemcitabine Hydrochloride; Gold Au 198; Hydroxyurea; Idarubicin
Hydrochloride; Ifosfamide; Imofosine; Interferon Alfa-2a;
Interferon Alfa-2b ; Interferon Alfa-n1; Interferon Alfa-n3;
Interferon Beta-Ia; Interferon Gamma-Ib; 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; Sparsomycinl,
Spirogermanium Hydrochloride; Spiromustine; Spiroplatin;
Streptonigrin; Streptozocin; Strontium Chloride Sr 89; Sulofenur;
Talisomycin; Taxane; Taxoid; Tecogalan Sodium; Tegafur;
Teloxantrone Hydrochloride; Temoporfin; Teniposide; Teroxirone;
Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofurin;
Tirapazamine; Topotecan Hydrochloride; 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.
[0081] Other anti-neoplastic compounds include: 20-epi-1,25
dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;
acyiflilvene; 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-DLPTBA;
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; capecitabine;
carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN
700; cartilage derived inhibitor; carzelesin; casein kinase
inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
chlorins; 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;
dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B;
didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-;
dioxamycin; diphenyl spiromustine; 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; gleevec; 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-; irinotecan; 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 compounds; 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;
mirimostirn; 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 agent; 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; riilutamide; nisamycin; nitric oxide
modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine;
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral cytokine inducer; ormiaplatin; osaterone;
oxaliplatin; oxaunomycin; 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
compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; 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; rohituuine; romurtide; roquinimex; rubiginone B 1;
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;
sizofiran; 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;
thalidomide; thiocoraline; thrombopoietin; thrombopoietin mimetic;
thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid
stimulating hormone; tin ethyl etiopurpurin; tirapazamine;
titanocene dichloride; topotecan; topsentin; toremifene; totipotent
stem cell factor; translation inhibitors; tretinoin;
triacetyluridine; triciribine; trimetrexate; triptorelin;
tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins;
UBC inhibitors; ubeniinex; 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; zinostatin
stimalamer.
[0082] Anti-cancer supplementary potentiating agents include:
tricyclic anti-depressant drugs (e.g., imipramine, desipramine,
amitryptyline, clomipramine, trimipramine, doxepin, nortriptyline,
protriptyline, amoxapine and maprotiline); non-tricyclic
anti-depressant drugs (e.g., sertraline, trazodone and citalopram);
Ca.sup.2+ antagonists (e.g., verapamil, nifedipine, nitrendipine
and caroverine); calmodulin inhibitors (e.g., prenylamine,
trifluoroperazine and clomipramine); Amphotericin B; Triparanol
analogues (e.g., tamoxifen); antiarrhythmic drugs (e.g.,
quinidine); antihypertensive drugs (e.g., reserpine); Thiol
depleters (e.g., buthionine and sulfoximine) and Multiple Drug
Resistance reducing agents such as Cremaphor EL.
[0083] The compounds of the invention also can be administered with
cytokines such as granulocyte colony stimulating factor or
anti-sense oligonucleotides such as, but not limited to, Bcl-2,
HIAP1, HIAP2, XIAP or survivin.
[0084] The conjugates of the invention also are useful, in general,
for treating mammalian cell proliferative disorders other than
cancer, including psoriasis, actinic keratosis, inflammation,
etc.
[0085] The use of any of the compounds having the structure of
formula I, II and III for treatment of cancer, inflammation, or
symptoms related thereto is also encompassed by the invention.
General Preparative Methods
[0086] The compounds of the invention may be prepared by use of
known chemical reactions and procedures. Nevertheless, the
following general preparative methods are presented to aid the
reader in synthesizing compounds of formula I, II and III.
Substitution patterns have been minimized for convenience except
where clarification is required. However, all combinations of
substitution are implicit in the methodologies outlined below.
[0087] The invention encompasses intermediates for manufacturing
the compounds of formula I, II and III, as described herein.
Mixtures including isomeric mixtures also may result depending upon
the symmetry of the starting molecule. Such mixtures are within the
scope of the invention.
[0088] To prepare the full range of compounds of the invention,
only the chemistry described below, together with chemistry known
to those of skilled in the art is required. In particular,
modifications of the core structures can be accomplished using
routine chemistry such as described herein.
Preparative Methods
[0089] Compound 121 was prepared using a similar method to that
previously described in PCT/CA01/00718. The N-substituted indole
3-glyoxylate B121 was prepared by the alkylation of intermediate B1
with (3-bromopropoxy)-tert-butyldimethylsilane using NaH in DMF.
Condensation of glyoxylate B121 and acetamide C1 using 3.0 equiv of
1.0 M potassium tert-butoxide in THF, followed by quenching the
reaction with concentrated HCl afforded 121 in good yields.
##STR10##
[0090] Compound 121 may be directly functionalized at the alcohol
position by mesylation to form mesylate 121 (MES121), and treatment
with a variety of nucleophiles such as, but not limited to, azide,
mono- and disubstituted amines, thiourea, and 2-imidazolidone.
##STR11##
[0091] In this way a variety of substituted derivates may be
prepared, typified by compounds such as compound 133, 143, and 156.
##STR12## Staudinger reduction of the azide 161 with
triphenylphosphine/water yields the primary amines 162 as shown
below. ##STR13##
[0092] The following compounds were prepared, and particulars of
functional groups are provided in Table 15. TABLE-US-00001 TABLE 15
Exemplary compounds ##STR14## Bond be- Ex- tween am- X.sup.5/ ple
X.sup.10 R.sup.3 R.sup.50 R.sup.7 X.sup.5/R.sup.5 X.sup.9 X.sup.10
121 d H --OH H CH CH CH 124 d BnO --OH H CH CH CH 125 d H --OH H
CMe CH CH 126 d H --OH BnO CH CH CH 127 d H --OH H CH CH CMe 128 d
H --OH H N CH CH 129 d BnO --OH H CMe CH CH 130 d H --OH H CH N CH
131 d BnO --OH H CH CH CMe 132 d H --OH F CH CH CH 133 d H
--N(CH.sub.3).sub.2 H CH CH CH 136 d BnO --N(CH.sub.3).sub.2 H CH
CH CH 137 d H --N(CH.sub.3).sub.2 H CMe CH CH 138 d H
--N(CH.sub.3).sub.2 BnO CH CH CH 139 d H --N(CH.sub.3).sub.2 H CH
CH CMe 140 d H --N(CH.sub.3).sub.2 H N CH CH 141 d BnO
--N(CH.sub.3).sub.2 H CMe CH CH 142 d H --N(CH.sub.3).sub.2 H CH N
CH 143 d H --SC(.dbd.NH)NH.sub.2 H CH CH CH 146 d H
--SC(.dbd.NH)NH.sub.2 H CMe CH CH 147 d H --SC(.dbd.NH)NH.sub.2 BnO
CH CH CH 148 d BnO --SC(.dbd.NH)NH.sub.2 H CH CH CH 149 d BnO
--SC(.dbd.NH)NH.sub.2 H CH C CH Me 150 d BnO --SC(.dbd.NH)NH.sub.2
H CH CH CMe 151 d H --SC(.dbd.NH)NH.sub.2 H CH CH CMe 152 d H
--SC(.dbd.NH)NH.sub.2 H CH N CH 153 d MeO --SC(.dbd.NH)NH.sub.2 H
CH CH CH 154 d F --SC(.dbd.NH)NH.sub.2 H CH CH CH 155 d H
--SC(.dbd.NH)NH.sub.2 F CH CH CH 156 d H --Z H CH CH CH 159 s H
--SC(.dbd.NH)NH.sub.2 H CH.sub.2 CH CH.sub.2 160 d OCH.sub.2SPh
--SC(.dbd.NH)NH.sub.2 H CH CH CH 161 d H --N.sub.3 H H CH CH 162 d
H --NH.sub.2 H H CH CH d = double bond, s = single bond Me =
--CH.sub.3, Bn = --CH.sub.2Ph, Z = ##STR15##
[0093] The introduction of a 3-hydroxypropyl moiety at the C3
position of the right hand "reverse-indole" was accomplished in the
following manner. Methyl 3-indolepropionate was reduced with DIBAL
to the corresponding alcohol, silylated with TBDMSC1 and converted
to acetamide C163 in the usual manner with NaH and iodoacetamide.
##STR16## Base mediated cyclization of B1 and C163 using KO.sup.tBU
in THF provided compound 163. ##STR17##
[0094] As before, functionalization of compounds 163 and 164 with
methanesulfonic anhydride provided intermediates MIES163 and
MIES164. Displacement of the mesylate with various nucleophiles
yields a variety of substituted derivatives. ##STR18##
[0095] These compounds are summarized below, and examples are
provided in TABLE 16. TABLE-US-00002 TABLE 16 ##STR19## Exemplary
Compounds Example R.sup.3 R.sup.50 R.sup.7 R.sup.4 163 H OH H H 164
H OH H Me 165 BnO OH H H 166 H SC(.dbd.NH)NH.sub.2 H H 167 H
SC(.dbd.NH)NH.sub.2 H Me 168 BnO SC(.dbd.NH)NH.sub.2 H Me 169 H
N(CH.sub.3).sub.2 H Me 170 H Z H Me 171 H N.sub.3 H Me 172 H
NH.sub.2 H Me
[0096] The dimethlyamino compounds were submitted as the free base,
whereas the thioamidino and Z compounds were submitted as the
methanesulfonic acid salts. Preferred embodiments include those
compounds substituted at R.sup.5 with an alkylthioamidino meoity as
seen in compounds 166, 167, and 168.
Anti-Cancer Activity
[0097] Select compounds were tested for their ability to kill
various cancer cell lines. Additionally, we investigated the
ability of these compounds to sensitize cancer cell lines to
apoptosis in the presence of death ligands.
[0098] Prostate cancer is often resistant to traditional
chemotherapies. DU145 is representative prostated cancer cell line.
DU145 cells were cultured in the presence of various concentrations
of compound 136. Compound 136 kills 100% of the cells at 10 .mu.M,
with an IC.sub.50 of approximately 7 .mu.M.
[0099] H460 is representative of a breast cancer cell line. H460
cells were cultured in the presence of various concentrations of
compound 167 and displayed an IC.sub.50 of approximately 3 .mu.M,
after a 24 hours treatment.
[0100] One mechanism of cellular apoptosis is regulated through
extra-cellular ligand/receptor interactions. The death receptors of
the tumor necrosis factor receptor (TNFR) family include TNFR1, FAS
(CD95), DR3/WSL, and the TRAIL/APO-2L receptors (TRAIL-R1/DR1,
TRAIL-R2/DR5). The binding of the death receptors by their
respective ligands, TNF or lymphotoxin, Fas-ligand/Fas-L, DR3 or
TRAIL/APO-2L, respectively, signals for the activation of their
respective apoptotic mechanisms. Several cancer cell lines have
become resistant to TNFR related apoptosis.
[0101] Jurkats are a T-cell derived lymphoma cell line which
expresses both FAS receptor and Fas-L. These cells, however, are
only mildly sensitive to Fas-L/anti-Fas induced apoptosis. Select
compounds were tested for their ability to kill jurkats.
Additionally, we investigated the ability of select compounds to
sensitize jurkats to anti-Fas mediated apoptosis.
[0102] As shown in TABLE 18, select compounds of this class kill
jurkats at concentrations of 3-10 .mu.M. anti-Fas (5 ng/mL) kills
48% of the cells after 19 hours. When cultured in the presence of
compound and anti-Fas (5 ng/mL) increased levels of apoptosis were
observed at lower compound concentrations. This 2-3 fold shift in
the dose response represents a synergistic effect of compound and
anti-Fas, suggesting that compound may be augmenting the FAS
mediated death pathway. FIG. 2 depicts the killing of cultured
Jurkats with compounds 167 and 168 (.+-.anti-Fas), and further data
are provided in TABLE 18. TABLE-US-00003 TABLE 18 Killing of
cultured Jurkats with and without anti-Fas Survival % Without With
Example Dose Anti-Fas Anti-Fas 145 10 11 -- 3 93 35 146 10 0 -- 3
>90 20 147 10 0 -- 3 >90 20 148 10 0 20 3 >90 149 10 0 --
3 >90 2 150 10 0 -- 3 >90 5 159 10 17 -- 3 >90 10 167 30 0
0 10 0 0 3 50 5 1 88 17 0.3 98 43 168 30 0 0 10 1 0 3 46 1 1 89 49
0.3 91 49
[0103] Taken together, the above results demonstrate that compound
represented by formula I, II and III represent potent anti-cancer
agents. Select compounds of this class kill prostate and breast
cancer cells. Additionally, select compound of this class kill
and/or sensitize jurcats to apoptosis induced by anti-Fas, in a
dose dependent manner. These compounds are useful in the treatment
of cancer and inflammation.
Experimental Procedures
[0104] Select indole glyoxylate (B) and indole acetamide (C)
intermediates were prepared as previously described
(PCT/CA01/00718).
EXAMPLE 121
3-(1-(3-hydroxypropyl)indol-3-yl)-4-(indol-1-yl)-pyrrole-2,5-dione
Step 1
[0105] Intermediate B1 (5.24 g, 25.9 mmol) was added to a
suspension of NaH (1.13 g, 28.4 mmol) in DMF (100 mL), cooled to
0.degree. C. After 1 h (3-bromopropoxy)-tert-butyldimetylsilane
(6.40 g, 26.0 mmol) was added and the resultant mixture was stirred
for 12 h at RT. A saturated aqueous solution of ammonium chloride
and ethyl acetate were added, the organic layer was separated,
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure. Purification by silica gel
chromatography, eluting with 1:1 ethyl acetate/hexane, afforded
intermediate B121 as a yellow solid.
Step 2
[0106] Intermediates B121 (5.24 g, 13.97 mmol) and intermediate C1
(1.21 g, 6.98 mmol) were dissolved in THF (100 mL) and treated with
a 1.0M THF solution of .sup.tBuOK (21.0 mL, 21.0 mmol). The
resulting suspension was stirred for 12 h at RT. The reaction was
quenched by the addition of concentrated HCl (5 mL) and diluted
with ethyl acetate. Water was added and the organic layer was
separated and washed with aqueous NaHCO.sub.3 and brine, dried over
MgSO.sub.4, filtered, and concentrated under reduced pressure.
Purification by silica gel chromatography, eluting with 1:1 ethyl
acetate/hexane, afforded compound 121 as an orange solid. .sup.1H
NMR (200 MHz, DMSO-d.sup.6) .delta. 8.06 (s, 1H), 7.53-7.56 (m,
2H1), 7.41 (d, J=8.3 Hz, 1H), 6.73-6.98 (m, 5H), 6.49 (t, J=7.6 Hz,
1H), 6.02 (d, J=8.0 Hz, 1H), 4.66 (t, J=4.9 Hz, 1H), 4.31 (t, J=6.6
Hz, 2H), 3.36 (J=5.6 Hz, 2H), 1.91-1.83 (m, 2H).
[0107] Compound 124 to 132 were prepared as per compound 121 using
the corresponding intermediates B and C.
EXAMPLE 124
3-(5-benzyloxy-1-(3-hydroxypropyl)indol-3-yl)-4-(indol-1-yl)-pyrrole-2,5-d-
ione
[0108] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.11 (s, 1H),
7.57 (d, J=8.0 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.35-7.26 (m, 4H),
7.17-7.10 (m, 3H), 7.05-6.92 (m, 2H), 6.72 (d, J=4.0 Hz, 1H), 6.64
(d, J=8.0 Hz, 1H), 5.55 (s, 1H), 4.65 (t, J=4.0 Hz, 1H), 4.29 (t,
J=6.0 Hz, 2H), 4.01 (s, 2H), 3.38-3.31 (m, 2H), 1.87 (t, J=6.0 Hz,
1H)
EXAMPLE 125
3-(1-(3-hydroxypropyl)indol-3-yl)-4-(3-methylindol-1-yl)-pyrrole-2,5-dione
[0109] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 7.99 (s, 1H),
7.49-7.34 (m, 3H), 6.99-6.92 (m, 2H), 6.85-6.75 (m, 2H), 6.51 (t,
J=8.0 Hz, 1H), 6.12 (d, J=8.0 Hz, 1H), 4.64 (t, J=6.0 Hz, 1H), 4.30
(t, J=6.0 Hz, 11H), 3.38-3.30 (m, 2H), 2.28 (s, 3H), 1.85(t, J=6.0
Hz, 2H)
EXAMPLE 126
3-(5-benzyloxyindol-1-yl)-4-(1-(3-hydroxypropyl)indol-3-yl)-pyrrole-2,5-di-
one
[0110] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.01 (s, 1H),
7.49-7.24 (m, 8H), 7.12-6.79 (m, 3H), 6.64-6.49 (m, 2H), 6.08 (d,
J=8.0 Hz, 1H), 4.99 (s, 2H), 4.64 (t, J=6.0 Hz, 1H), 4.30 (t, J=8.0
Hz, 1H), 3.37-3.30 (m, 2H), 1.92-1.85 (m, 2H).
EXAMPLE 127
3-(1-(3-hydroxypropyl)indol-3-yl)-4-(2methylindol-1-yl)-pyrrole-2,5-dione
[0111] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.21 (s, 1H),
7.46-7.41 (m, 2H), 7.02-6.85 (m, 4H), 6.54-6.45 (m, 2H), 5.92 (d,
J=8.0 Hz, 1H), 4.63 (t, J=6.0 Hz, 1H), 4.30 (t, J=8.0 Hz, 2H),
3.36-3.27 (m, 2H), 1.90-1.79 (m, 2H)
EXAMPLE 128
3-(benzimidazol-1-yl)-4-(1-(3-hydroxypropyl)indol-3-yl)-pyrrole-2,5-dione
[0112] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.39 (s, 1H),
8.11 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H),
7.20-7.10 (m, 1H), 7.04-6.98 (m, 3H), 6.54 (t, J=8.0 Hz, 1H), 6.06
(d, J=8.0 Hz, 1H), 4.64 (t, J=6.0 Hz, 1H), 4.32 (t, J=6.0 Hz, 2H),
3.37-3.30 (m, 2H), 1.90-1.86 (m, 2H)
EXAMPLE 129
3-(5-benzyloxy-1-(3-hydroxypropyl)indol-3-yl)-4-(3-methylindol-1-yl)-pyrro-
le-2,5-dione
[0113] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.10 (s, 1H),
7.54-7.28 (m, 6H), 7.19-7.14 (m, 2H), 7.03-6.85 (m, 3H), 6.60 (dd,
J=8.0, 2.0 Hz, 1H), 5.57 (d, J=2.0 Hz, 1H), 4.64 (t, J=4.0 Hz, 1H),
4.28 (t, J=6.0 Hz, 2H), 4.06 (s, 2H), 3.40-3.30 (m, 2H), 2.21 (d,
J=2.0 Hz, 3H), 1.87 (t, J=6.0 Hz, 1H).
EXAMPLE 130
3-(7-azaindol-1-yl)-4-(1-(3-hydroxypropyl)indol-3-yl)-
pyrrole-2,5-dione
[0114] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.15 (s, 1H),
7.98 (d, J=8.0 Hz, 1H), 7.93 (d, J=4.0 Hz, 1H), 7.63 (d, J=4.0 Hz,
1H), 7.40 (d, J=8.0 Hz, 1H1), 7.05-6.92 (m, 2H), 6.74 (d, J=4.0 Hz,
1H), 6.45 (t, J=8.0 Hz, 1H), 5.86 (d, J=8.0 Hz, 1H), 4.64 (t, J=2.0
Hz, 1H), 4.29 (t, J=6.0 Hz, 2H), 3.35-3.31 (m, 2H), 1.96-1.81 (m,
2H).
EXAMPLE 131
3-(5-benzyloxy-1-(3-hydroxypropyl)indol-3-yl)-4-(2-methylindol-1-yl)-pyrro-
le-2,5-dione
[0115] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.24 (s, 1H),
7.47-7.13 (m, 7H), 7.01-6.97 (m, 3H), 6.68 (dd, J=8.0, 2.0 Hz, 1H),
6.43 (s, 1H), 5.55 (d, J=2.0 Hz, 1H), 4.62 (t, J=6.0 Hz, 1H), 4.29
(t, J=8.0 Hz, 2H), 3.97 (d, J=10.0 Hz, 1H), 3.85 (d, J=10.0 Hz,
1H), 3.37-3.29 (m, 2H), 2.11 (s, 3H), 1.96-1.81 (m, 2H).
EXAMPLE 132
3-(5-Fluoroindol-1-yl)-4-(1-(3-hydroxypropyl)indol-3-yl)-
pyrrole-2,5-dione
[0116] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.06 (s, 1H),
7.60 (d, J=2.40 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.31 (dd, J=9.6,
2.4 Hz, 1H), 7.00-6.86 (m, 2H), 6.72-6.48 (m, 2H), 6.50 (t, J=8.0
Hz, 1H), 5.97 (d, J=8.0 Hz, 1H), 4.63 (t, J=4.0 Hz, 1H), 4.31 (t,
J=6.0 Hz, 2H), 1.36-3.29 (m, 2H), 1.96-1.83 (m, 2H).
EXAMPLE 133
3-(1-(3-dimethylaminopropyl)indol-3-yl)-4-(indol-1-yl)-pyrrole-2,5-dione
Step one:
[0117] A solution of compound 121 (250 mg, 0.65 mmol) in THF (10
mL) was reacted with pyridine (157 .mu.L, 1.94 mmol) and
methanesulfonic anhydride (136 mg, 0.78 mmol) and stirred for 12 h
at RT. Saturated aqueous ammonium chloride was added, the organic
layer was separated, the aqueous phase was extracted with ethyl
acetate, the combined organic extracts were washed with brine,
dried over MgSO.sub.4, filtered, and concentrated under reduced
pressure. Purification by flash chromatography (silica gel, ethyl
acetate) afforded the intermediate MES121 as an orange solid.
Step two:
[0118] Dimethylamine (2.8 mL, 5.6 mmol, 2.0 M in THF) was added to
a solution of intermediate MES 121 (150 mg, 0.32 mmol) in THF (5
mL) and the reaction was stirred for 4 days at RT. Saturated
aqueous ammonium chloride (20 mL) and ethyl acetate were added, the
layers were separated, the aqueous layer was extracted with ethyl
acetate, the combined organic extracts were washed with brine,
dried over MgSO.sub.4, filtered, and concentrated under reduced
pressure. Purification by flash chromatography (silica gel,
ethylacetate) afforded the expected compound as an orange
solid.
[0119] .sup.1H NMR (200 Mz, DMSO-d.sup.6) .delta. 8.03 (s, 1H),
7.57-7.52 (m, 2H), 7.41 (d, J=8.3 Hz, 1H), 6.99 -6.73 (m, 5H),
6.52-6.47 (m, 1H), 6.04 (d, J=8.1 Hz, 1H), 4.28 (t, J=6.5 Hz, 2H),
2.11 (s, 6H), 2.07 (t, =6.5 Hz, 2H), 1.88-1.79 (m, 2H).
[0120] Compound 136 to 142 were prepared as per compound 133 using
the corresponding alcohol.
EXAMPLE 136
3-(5-benzyloxy-1-(3-dimethylaminopropyl)indol-3-yl)-4-(indol-1-yl)-pyrrole-
-2,5-dione
[0121] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.10 (s, 1H),
7.57 (d, J=4.0 Hz, 1H), 7.49 (d, J=4.0 Hz, 1H), 7.37-7.27 (m, 2H),
7.17-6.93 (m, 3H), 6.72 (d, J=2.0 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H),
5.56 (s, 1H), 4.30-4.20 (m, 2H), 4.05 (s, 2H), 2.14 (s, 6H),
2.13-2.02 (m, 2H), 1.85-1.75 (m, 2H).
EXAMPLE 137
3-(1-(3-dimethylaminopropyl)indol-3-yl)-4-(3-methylindol-1-yl)-pyrrole-2,5-
-dione
[0122] .sup.1H NMR (200 Mhz, DMSO-d.sup.6) .delta. 7.95 (s, 1H),
7.49-7.34 (m, 3H), 6.99-6.91 (m, 2H), 6.81-6.72 (m, 2H), 6.51 (t,
J=8.0 Hz, 1H), 6.15 (d, J=8.0 Hz, 1H), 4.25 (t, J=6.0 Hz, 2H), 2.28
(s, 3H), 2.09 (s, 6H), 2.08-2.03 (m, 2H), 1.86-1.76 (m, 2H).
EXAMPLE 138
3-(5-benzyloxyindol-1-yl)-4-(1-(3-dimethylaminopropyl)indol-3-yl)-pyrrole--
2,5-dione
[0123] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 7.97 (s, 1H),
7.49-7.30 (m, 1H), 7.12 (s, 1H), 6.98 (t, J=8.0 Hz, 1H), 6.80 (d,
J=10.0 Hz, 1H), 6.64-6.46 (m, 3H), 6.11 (d, J=8.0 Hz, 1H), 4.99 (s,
2H), 4.30-4.25 (m, 2H), 2.09 (s, 6H), 2.08-2.01 (m, 6H), 1.85-1.78
(m, 2H).
EXAMPLE 139
3-(1-(3-dimethylaminopropyl)indol-3-yl)-4-(2-methylindol-1-yl)-pyrrole-2,5-
-dione
[0124] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.16 (s, 1H),
7.45-7.41 (m, 2H), 7.03-6.81 (m, 4H), 6.55-6.45 (m, 2H), 5.97 (d,
J=8.0 Hz, 1H), 4.26 (t, J=6.0 Hz, 2H), 2.21 (s, 3H), 2.08 (s, 6H),
2.08-1.99 (m, 2H), 1.96-1.85 (m, 2H).
EXAMPLE 140
3-(benzimidozol-1-yl)-4-(1-(3-dimethylaminopropyl)indol-3-yl)-pyrrole-2,5--
dione
[0125] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.41 (s, 1H),
8.08 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H),
7.16-6.96 (m, 4H), 6.54 (t, J=8.0 Hz, 1H), 6.10 (d, J=8.0 Hz, 1H),
4.28 (t, J=6.0 Hz, 1H), 2.10 (s, 6H), 2.08-2.01 (m, 2H), 1.88-1.75
(m, 2H).
EXAMPLE 141
3-(3-methylindol-1-yl)-4-(5-benzyloxy-1-(3-dimethylaminopropyl)indol-3-yl)-
-pyrrole-2,5-dione
[0126] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.08 (s, 1H),
7.48 (d, J=8.0Hz, 1H), 7.37-7.28 (m, 5H), 7.20-7.16 (m, 2H),
7.02-6.90 (m, 3H), 6.59 (dd, J=8.0, 2.0 Hz, 1H), 5.57 (d, J=2.0 Hz,
1H), 4.25 (t, J=8.0 Hz, 2H), 4.07 (s, 2H), 2.21 (s, 3H), 2.10 (s,
3H), 2.09-1.99 (m, 2H), 1.88-1.80 (m, 2H); .sup.13C NMR (50 MHz,
DMSO-d.sup.6) .delta. 196.1, 194.5, 178.1, 162.1, 159.3, 155.9,
153.7, 153.5, 152.8, 152.6, 151.5, 151.2, 150.3, 147.2, 145.5,
143.7, 138.7, 138.3, 136.8, 136.4, 127.9, 127.7, 93.8, 80.5, 70.1,
68.9, 52.3, 34.4.
EXAMPLE 142
3-(7-azaindol-1-yl)-4-(1-(3-dimethylaminopropyl)indol-3-yl)-pyrrole-2,5-di-
one
[0127] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.12 (s, 1H),
7.98 (d, J=10.0 Hz, 1H), 7.91 (d, J=6.0 Hz, 1H), 7.64 (d, J=4.0 Hz,
1H), 7.40 (d, J=8.0 Hz, 1H), 7.05-6.92 (m, 2H), 6.74 (d, J=4.0 Hz,
1H), 6.45 (t, J=8.0 Hz, 1H), 5.89 (d, J=8.0 Hz, 1H), 4.25 (t, J=8.0
Hz, 1H), 2.09 (s, 6H), 2.09-2.01 (m, 2H), 1.85-1.78 (m, 2H).
EXAMPLE 143
3-(3-((amidiothio)propyl)indol-3-yl)-4-(indol-1-yl)-pyrrole-2,5-dione
[0128] Intermediate MES121 (464 mg, 1 mmol) and thiourea (114 mg,
1.5 mmol) in ethanol (10 mL) was heated to reflux for 18 h. The
solvent was removed in vacuo and the residue was purified by
recrystallization from ethyl acetate to provide compound 143 as an
orange solid. .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 7.95 (s,
1H), 7.47-7.53 (m, 2H), 7.39 (d, J=4.0 Hz, 1H), 7.01-6.70 (m, 5H),
6.50 (t, J=8.0 Hz, 1H), 6.06 (d, J=8.0 Hz, 1H), 4.38-4.21 (m, 2H),
3.05-2.88 (m, 2H), 2.37 (s, 3H), 2.18-1.98 (m, 2H).
[0129] Compound 146 to 155 and 159, 160 were prepared as per
compound 143 using the corresponding mesylate.
EXAMPLE 146
3-(3-((amidiothio)propyl)indol-3-yl)-4-(3-methylindol-1-yl)-pyrrole-2,5-di-
one
[0130] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 9.07 (s, 3H),
7.94 (s, 1H), 7.49-7.33 (m, 3H), 7.02-6.93 (m, 2H), 6.81-6.76 (m,
2H), 6.54 (t, J=8.0 Hz, 1H), 6.21 (d, J=8.0 Hz, 1H), 4.38-4.22 (m,
2H), 3.10-2.98 (m, 2H), 2.34 (s, 3H), 2.27 (s, 3H), 2.10-2.02 (m,
2H).
EXAMPLE 147
3-(3-((amidiothio)propyl)indol-3-yl)-4-(5-benzyloxyindol-1-yl)-pyrrole-2,5-
-dione
[0131] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 9.05 (s, 3H),
8.02 (s, 1H), 7.49-7.27 (m, 7H), 7.13 (d, J=2.0 Hz, 1H), 7.01 (t,
J=8.0 Hz, 1H), 6.83 (d, J=10.0 Hz, 1H), 6.64-6.48 (m, 3H), 6.10 (d,
J=10.0 Hz, 1H), 4.99 (s, 2H), 4.40-4.25 (m, 2H), 3.05 (t, J=6.0 Hz,
2H), 2.31 (s, 3H), 2.15-2.01 (m, 2H).
EXAMPLE 148
3-(3-((amidiothio)propyl)-5-benzyloxyindol-3-yl)-4-(indol-1-yl)-pyrrole-2,-
5-dione
[0132] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 9.05 (s, 3H),
8.10 (s, 1H), 7.57 (d, J=4.0 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H),
7.38-7.27 (m, 5H), 7.15-7.12 (m, 3H), 7.06-6.91 (m, 3H), 6.72 (d,
J=2.0 Hz, 1H), 6.65 (d, J=10.0 Hz, 1H), 5.58 (s, 1H), 4.38-4.28 (m,
2H), 4.02 (s, 2H), 3.07 (t, J=6.0 Hz, 2H), 2.32 (s, 3H), 2.10-2.02
(m, 2H).
EXAMPLE 149
3-(3-((amidiothio)propyl)-5-benzyloxyindol-3-yl)-4-(3-methylindol-1-yl)-py-
rrole-2,5-dione
[0133] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 9.06 (s, 3H),
8.10 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.36-7.28 (m, 4H), 7.19-7.15
(m, 2H), 7.03-6.86 (m, 3H), 6.61 (dd, J=10.0, 2.0 Hz, 1H), 5.61 (d,
J=2.0 Hz, 1H), 4.35-4.25 (m, 2H), 4.08 (s, 2H), 3.06 (t, J=6.0 Hz,
2H), 2.33 (s, 3H), 2.22 (s, 3H), 2.18-2.02 (m, 2H).
EXAMPLE 150
3-(3-((amidiothio)propyl)-5-benzyloxyindol-3-yl)-4-(2-methylindol-1-yl)-py-
rrole-2,5-dione
[0134] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 9.03 (s, 3H),
8.25 (s, 1H), 7.45-7.30 (m, 5H), 7.20-7.13 (m, 3H), 7.01-6.96 (m,
3H), 6.71 (d, J=8.0 Hz, 1H), 6.44 (s, 1H), 5.58 (s, 1H), 4.36-4.30
(m, 2H), 4.00 (d, J=12.0 Hz, 1H), 3.87 (d, J=12.0 Hz, 1H),
3.09-3.02 (m, 2H), 2.31 (s, 3H), 2.12 (s, 3H), 2.12-2.02 (m,
2H).
EXAMPLE 151
3-(3-((amidiothio)propyl)indol-3-yl)-4-(2-methylindol-1-yl)-pyrrole-2,5-di-
one
[0135] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 9.06 (s, 3H),
8.18 (s, 1H), 7.48-7.43 (m, 2H), 7.05-6.80 (m, 4H), 6.58-6.46 (m,
2H), 6.00 (d, J=8.0 Hz, 1H), 4.38-4.25 (m, 2H). 3.15-2.98 (m, 2H),
2.34 (s, 3H), 2.22 (s, 3H), 2.08-1.99 (m, 2H).
EXAMPLE 152
3-(3-((amidiothio)propyl)indol-3-yl)-4-(7-azaindol-1-yl)-pyrrole-2,5-dione
[0136] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 9.03 (s, 3H),
8.15 (s, 1H), 7.63 (d, J=4.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H),
7.04-6.97 (m, 2H), 6.74 (d, J=2.0 Hz, 1H), 6.46 (t, J=8.0 Hz, 1H),
5.90 (d, J=8.0 Hz, 1H), 4.35-4.30 (m, 2H), 3.10-3.02 (m, 2H), 2.31
(s, 3H), 2.10-2.02 (m, 2H).
EXAMPLE 153
3-(3-((amidiothio)propyl)-5-methoxyindol-3-yl)-4-(indol-1-yl)-pyrrole-2,5--
dione
[0137] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.07 (s, 1H),
7.55 (d, J=8.0 Hz, 1H), 7.49 (d, J=4.0 Hz, 1H), 7.33 (d, J=8.0 Hz,
1H), 7.08-6.88 (m, 4H), 6.68 (d, J=2.0 Hz, 1H), 6.56 (d, J=7.0 Hz,
1H), 5.52 (s, 1H), 4.35-4.30 (m, 2H), 3.10-3.01 (m, 2H), 2.92 (s,
3H), 2.33 (s, 3H), 2.10-2.00 (m, 2H).
EXAMPLE 154
3-(3-((amidiothio)propyl)-5-fluoroindol-3-yl)-4-(indol-1-yl)-pyrrole-2,5-d-
ione
[0138] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 9.03 (s, 3H),
8.05 (s, 1H), 7.54-7.44 (m, 3H), 6.96-6.76 (m, 5H), 5.68 (d, J=8.0
Hz, 1H), 4.38-4.23 (m, 2H), 3.15-2.98 (m, 2H), 2.31 (s, 3H),
2.08-1.98 (m, 2H).
EXAMPLE 155
3-(3-((amidiothio)propyl)indol-3-yl)-4-(5-fluoroindol-1-yl)-pyrrole-2,5-di-
one
[0139] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 9.08 (s, 3H),
8.05 (s, 1H), 7.60 (d, J=4.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.32
(d, J=8.0 Hz, 1H), 7.00-6.90 (m, 2H), 6.73-6.50 (m, 3H), 6.02 (d,
J=8.0 Hz, 1H), 4.42-4.25 (m, 2H), 3.15-2.99 (m, 2H), 2.34 (s, 3H),
2.07-1.99 (m, 2H).
EXAMPLE 156
3-(3-((dihydroimidazol-2-yl)thio)propyl)-5-((phenylthio)methoxy)indol-3-yl-
)-4-(indol-1-yl)-pyrrole-2,5-dione
[0140] A mixture of intermediate MES 121 (464 mg, 1 mmol) and
imidazolidinone (123 mg, 1.2 mmol) in ethanol (10 mL) was heated to
reflux for 18 h. The solvent was removed in vacuo and the residue
was purified by recrystallisation from ethyl acetate.
[0141] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.02 (s, 1H),
7.55-7.42 (m, 3H), 7.03-6.71 (m, 5H), 6.52 (t, J=8.0 Hz, 1H), 6.08
(d, J=8.0 Hz, 1H), 4.42-4.28 (m, 2H), 3.84 (s, 4H), 3.18-3.06 (m,
2H), 2.29 (s, 3H), 2.20-2.10 (m, 2H).
EXAMPLE 159
3-(3-((amidiothio)propyl)indol-3-yl)-4-(indolin-1-yl)-pyrrole-2,5-dione
[0142] LCSM (m/z) M+1=446.
EXAMPLE 160
3-(3-((amidiothio)propyl)-5-((phenylthio)methoxy)indol-3-yl)-4-(indol-1-yl-
)-pyrrole-2,5-dione
[0143] LCSM (m/z) M+1=566.
EXAMPLE 161
3-(3-(azido)propyl)-5-((phenylthio)methoxy)indol-3-yl)-4-(indol-1-yl)-pyrr-
ole-2,5-dione
[0144] A mixture of intermediate MES121 (928 g, 2 mmol) and sodium
azide (260 mg, 4.0 mmol) in DMF (10 mL) was heated to reflux for 3
h. Water was added and the product was isolated by filtration to
provide compound 161 as an orange solid.
[0145] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.00 (s, 1H),
7.60-7.52 (m, 2H), 7.41 (d, J=10.0 Hz, 1H), 7.00-6.72 (m, 5H), 6.51
(t, J=8.0 Hz, 1H), 6.10 (d, J=8.0 Hz, 1H), 4.31 (t, J=6.0 Hz, 1H),
3.25 (t, J=8.0 Hz, 1H), 2.00-1.92 (m, 2H).
EXAMPLE 162
3-(3-aminopropyl)-5-((phenylthio)methoxy)indol-3-yl)-4-(indol-1-yl)-pyrrol-
e-2,5-dione
[0146] To a solution of compound 161 (670 mg, 1.63 mmol) in THF (10
mL) was added triphenylphosphine (469 mg, 1.79 mmol). The resulting
solution was stirred for 2 h at RT and then water was added (55
.mu.L, 3.06 mmol). After stirring for 12 h at RT the solvent was
removed in vacuo and the compound was purified by recrystallization
from ethyl acetate to provide compound 162 as an orange solid
[0147] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.03 (s, 2H),
7.60-7.44 (m, 4H), 6.98-6.71 (m, 5H), 6.48 (t, J=8.0 Hz, 1H), 6.00
9d, J=8.0 Hz, 1H), 4.42-3.96 (m, 2H), 2.75-2.68 (m, 2H), 2.10-2.01
(m, 2H).
EXAMPLE 163
3-(3-(3-hydroxypropyl)indol-1-yl)-4-(1-H-indol-3-yl)-4-pyrrole-2,5-dione
Step One:
[0148] 3-Indolepropionic acid (5 g) was dissolved in MeOH (50 mL)
and treated with conc. HCl (5 mL). The solution was stirred
overnight before the solvent was removed under reduced pressure to
provide methyl 3-indolepropionate in quantitative yield. Crude
methyl 3-indolepropionate (4.70 g, 23.2 mmol) was dissolved in THF
(50 mL), cooled to 0.degree. C., and treated with DIBAL-H (69.5 mL,
69.5 mmol). The reaction mixture was stirred for 2 h at 0.degree.
C. and then quenched by the slow addition of a saturated aqueous
solution of ammonium chloride and extracted with ethyl acetate, the
combined organic extracts were washed with brine, dried over
MgSO.sub.4, filtered, and concentrated under reduced pressure.
Purification by silica gel chromatography, eluting with 1:1 ethyl
acetate/hexane, afforded the 3-(3-hydroxypropyl)indole as a yellow
solid. .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 7.48 (d, J=8.0
Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.15-6.92 (m, 4H), 4.40 (t, J=6.0
Hz, 1H), 3.55 (t, J=6.0 Hz, 2H), 2.80 (t, J=8.0 Hz, 2H), 1.92-1.76
(m, 2H).
Step Two:
[0149] To a solution of 3-(3-hydroxypropyl)indole (1.75 g, 10 mmol)
in dichloromethane were sequentially added imidazole (748 mg, 11
mmol) and TBSCl (1.66 g, 11 mmol). The resultant mixture was
stirred for 3 h at RT. A saturated aqueous solution of NaHCO.sub.3
was added, the organic layer was separated, the aqueous phase was
extracted with ethyl acetate. The combined extracts were washed
with brine, dried over MgSO.sub.4, filtered, and concentrated under
reduced pressure. Purification by silica gel chromatography,
eluting with 1:4 ethyl acetate/hexane, afforded
3-(3-(tert-butyldimethylsiloxy)propyl)indole as a yellow solid.
.sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 7.45 (d, J=8.0 Hz, 1H),
7.22 (d, J=8.0 Hz, 1H), 7.15-6.92 (m, 4H), 3.65 (t, J=6.0 Hz, 2H),
2.70 (t, J=8.0 Hz, 2H), 1.92-1.76 (m, 2H), 0.86 (s, 9H), 0.01 (s,
6H).
Step Three:
[0150] 3-(3-(tert-Butyldimethylsiloxy)propyl)indole (2.60 g, 8.99
mmol) was added to a cooled suspension of NaH (395 mg, 9.89 mmol)
in DMF (30 mL). After stirring for 1 h at 0.degree. C.,
iodoacetamide (1.83 g, 9.89 mmol) was added and the resultant
mixture was stirred at RT for 12 h. The DMF was removed in vacuo
and the residue dissolved in ethyl acetate, water was added, the
organic phase was separated and washed with brine, dried over
MgSO.sub.4, filtered, and concentrated under reduced pressure.
Purification by silica gel chromatography, eluting with 1:4 ethyl
acetate/hexane, afforded intermediate C161 as a yellow solid.
.sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 7.48 (dd, J=8.0, 1.0
Hz, 1H), 7.26 (s, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.18 (s, 1H),
7.12-6.97 (m, 3H), 4.68 (s, 2H), 3.64 (t, J=6.0 Hz, 2H), 2.69 (t,
J=8.0 Hz, 2H), 1.90-1.74 (m, 2H), 0.89 (s, 9H), 0.01 (s, 6H).
Step Four:
[0151] tert-BuOK (8.6 mL, 1.0 M in 8.6 mmol) was added to a
suspension of intermediate C163 (1.16 g, 5.73 mmol) and
intermediate B1 (990 mg, 2.86 mmol) and the resulting mixture was
stirred at RT for 12 h. The reaction was quenched by the addition
of concentrated HCl (5 mL) and diluted with ethyl acetate. Water
was added, the organic layer was separated and washed with aqueous
NaHCO.sub.3 and brine, dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure. Purification by silica gel
chromatography, eluting with 1:4 ethyl acetate/hexane, afforded
compound 163 as an orange solid.
[0152] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 7.98 (s, 1H),
7.51 (d, J=8.0 Hz, 1H), 7.30 (s, 1H), 7.28 (d, J=6.0 Hz, 1H),
6.96-6.79 (m, 4H), 6.44 (t, J=8.0 Hz, 1H), 6.03 (d, J=8.0 Hz, 1H),
4.44 (t, J=4.0 Hz, 1H), 3.50-3.40 (m, 2H), 2.78-2.70 (m, 2H),
1.82-1.70 (m, 2H).
EXAMPLE 164
3-(3-(3-hydroxypropyl)indol-1-yl)-4-(1-methylindol-3-yl)-4-pyrrole-2,5-dio-
ne
[0153] Compound 164 was prepared as per compound 161 using methyl
3-(N-methylindole)glyoxylate in the place of intermediate B1 to
provide a yellow solid. .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta.
8.01 (s, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.36-7.31 (m, 2H), 7.00-6.82
(m, 4H), 6.46 (t, J=8.0 Hz, 1H), 5.93 (d, J=8.0 Hz, 1H), 4.45 (t,
J=6.0 Hz, 1H), 3.84 (s, 3H), 3.49-3.43 (m, 2H), 2.74 (t, J=6.0 Hz,
2H), 1.82-1.70 (m, 2H).
EXAMPLE 166
3-(3-(amidinothio)propyl)indol-1-yl)-4-(1-H-indol-3-yl)-4-pyrrole-2,5-dion-
e
Step One:
[0154] A solution of compound 163 (574 mg, 1.49 mmol) in THF (10
mL) was reacted with pyridine (361 .mu.L, 4.47 mmol) and
methanesulfonic anhydride (311 mg, 1.78 mmol) and stirred for 12 h
at RT. Saturated aqueous ammonium chloride was added, the organic
layer was separated, the aqueous phase was extracted with ethyl
acetate, the combined organic extracts were washed with brine,
dried over MgSO.sub.4, filtered, and concentrated under reduced
pressure. Purification by flash chromatography (silica gel, ethyl
acetate) afforded the intermediate MES163 as an orange solid.
[0155] .sup.1H NMR (DMSO-d.sup.6) .delta. 8.09 (s, 1H), 7.54 (d,
J=8.0 Hz, 1H), 7.35 (d, J=6.0 Hz, 1H), 7.34 (s, 1H), 7.00-6.84 (m,
4H), 6.48 (t, J=6.0 Hz, 1H), 5.93 (d, J=8.0 Hz, 1H), 4.20 (t, J=6.0
Hz, 1H), 3.85 (s, 3H), 3.14 (s, 3H), 2.80 (t, J=8.0 Hz, 2H),
2.05-1.94 (m, 2H).
[0156] Intermediate MES163 (477 mg, 1 mmol) and thiourea (114 mg,
1.5 mmol) in ethanol (10 mL) was heated to reflux for 18 h. The
solvent was removed in vacuo and the residue was purified by
recrystallization from ethyl acetate to provide compound 166.
[0157] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 9.03 (s, 3H),
8.00 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 7.29
(d, J=6.0 Hz, 1H), 7.05-6.85 (m, 4H), 6.41 (t, J=6.0 Hz, 1H), 5.98
(d, J=8.0 Hz, 1H), 3.41 (s, 3H), 3.15-3.10 (m, 2H), 2.90-2.80 (m,
2H), 2.02-1.92 (m, 2H).
EXAMPLE 167
3-(3-(amidinothio)propyl)indol-1-yl)-4(1-methylindol-3-yl)-4-pyrrole-2,5-d-
ione
[0158] Compound 167 was prepared as per compound 166 using
intermediate MES164 and thiourea. .sup.1H NMR (200 MHz,
DMSO-d.sup.6) .delta. 9.04 (s, 3H), 8.10 (s, 1H), 7.53 (d, J=8.0
Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 6.98-6.85 (m, 4H),
6.44 (t, J=8.0 Hz, 1H), 5.90 (d, J=8.0 Hz, 1H), 3.86 (s, 3H),
3.15-3.05 (m, 2H), 2.25-2.15 (m, 2H), 2.32 (s, 3H), 2.02-1.90 (m,
2H).
EXAMPLE 168
3-(3-(amidinothio)propyl)indol-1-yl)-4-(5-benzyloxy-1-methylindol-3-yl)-4--
pyrrole-2,5-dione
[0159] LCMS (m/z) M+1=550.2.
EXAMPLE 169
3-(3-(dimethylamino)propyl)indol-1-yl)-4-(1-methylindol-3-yl)-4-pyrrole-2,-
5-dione
[0160] Dimethylamine (20 mL, 40 mmol, 2.0 M in THF) was added to a
solution of intermediate MES 164 (954 mg, 2 mmol) in THF and the
reaction was stirred for 4 days at RT. Saturated aqueous ammonium
chloride (20 mL) and ethyl acetate were added, the layers were
separated, the aqueous layer was extracted with ethyl acetate, the
combined organic extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification by
flash chromatography (silica gel, ethylacetate) afforded the
expected compound as an orange solid.
[0161] .sup.1H NMR (200MHz, DMSO-d.sup.6) .delta. 8.09 (s, 1H),
7.50 (d, J=6.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.26 (s, 1H),
7.02-6.78 (m, 4H), 6.45 (t, J=8.0 Hz, 1H), 5.93 (d, J=8.0 Hz, 1H),
3.85 (s, 3H), 2.69 (t, J=8.0 Hz, 2H), 2.19 (t, J=8.0 Hz, 2H), 2.08
(s, 6H), 1.75-1.65 (m, 2H).
EXAMPLE 170
3-(3-((dihydroimidazol-2-yl)thio)propyl)indol-1-yl)-4-(1-methylindol-3-yl)-
-4-pyrrole-2,5-dione
[0162] A mixture of intermediate MES 164 (477 mg, 1 mmol) and
imidazolidinone (123 mg, 1.2 mmol) in ethanol (10 mL) was heated to
reflux for 18 h. The solvent was removed in vacuo and the residue
was purified by recrystallisation from ethyl acetate.
[0163] .sup.1H NMR (200 MHz, DMSO-d.sup.6) .delta. 8.09 (s, 1H),
7.53 (d, J=8.0 Hz, 1H), 7.38-7.29 (m, 2H), 7.03-6.82 (m, 4H), 6.44
(t, J=8.0 Hz, 1H), 5.89 (d, J=8.0 Hz, 1H), 3.84 (s, 4H), 3.42 (s,
3H), 3.20-3.10 (m, 2H), 2.85-2.72 (m, 2H), 2.30 (s, 3H), 2.08-1.84
(m, 2H).
EXAMPLE 171
3-(3-(azidopropyl)indol-1-yl)-4-(1-methylindol-3-yl)-4-pyrrole-2,5-dione
[0164] A mixture of intermediate MES164 (1.30 g, 2.72 mmol) and
sodium azide (354 mg, 5.45 mmol) in DMF (10 mL) was heated to
reflux for 3 h. Water was added and the product was isolated by
filtration to provide an orange solid. .sup.1H NMR (200 MHz,
DMSO-d.sup.6) .delta. 8.09 (s, 1H), 7.52 (d, J=6.0 Hz, 1H), 7.36
(d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.01-6.83 (m, 4H), 6.45 (t, J=8.0
Hz, 1H), 5.92 (d, J=8.0 Hz, 1H), 3.85 (s, 3H), 3.27 (t, J=6.0 Hz,
2H), 2.76 (t, J=6.0 Hz, 2H), 1.96-1.77 (m, 2H).
EXAMPLE 172
3-(3-(aminopropyl)indol-1-yl)-4-(1-methylindol-3-yl)-4-pyrrole-2,5-dione
[0165] To a solution of compound 171 (650 mg, 1.53 mmol) in TBF (10
mL) was added triphenylphosphine. The resulting solution was
stirred for 2 h at RT and then water was added (55 .mu.L, 3.06
mmol). After stirring for 12 h at RT, The solvent was removed in
vacuo and the compound was purified by cristallisation in ethyl
acetate to provide compound 172 as an orange solid. .sup.1H NMR
(200 MHz, DMSO-d.sup.6) .delta. 8.06 (s, 1H), 7.53 (d, J=8.0 Hz,
1H), 7.34 (s, 2H), 6.98-6.83 (m, 4H), 6.50-6.43 (m, 1H), 5.88 (d,
J=8.0 Hz, 1H), 3.82 (s, 3H), 2.84-2.76 (m, 4H), 1.98-1.89 (m,
2H).
EXAMPLE 173
Anticancer Effectiveness on Prostate Tumor Cells
[0166] Human prostate DU145 cells were cultured in 96 well dishes.
Cells were treated with various concentrations of test compounds
for 7 days. Media was then removed and replaced with fresh media
containing Alamar Blue. The cells were incubated for a further 4
hours and Alamar blue and conversion was assessed by fluorescence.
Compound effectiveness was determined by assessing the reduction in
Alamar blue bioconversion following 7 day treatment.
EXAMPLE 174
Sensitization of Fas Mediated Killing in Jurkat Cell Line
[0167] Human lymphoma jurkat cells were cultured in suspension in
24 well plates. Jurkat cell were treated with test compounds either
alone or in the presence of suboptimal doses of anti-Fas antibody.
After 18 hours of treatment cell death was assessed by Facs. Cells
were incubated with propidium iodide and the percentage of cells
that incorporated the stain was counted by Facs.
EXAMPLE 175
Anticancer Effectiveness on Lung Tumor Cells
[0168] Human lung H460 cells (7000 cells/well) were cultured in 96
well dishes. Cells were treated with various concentrations of test
compounds for 24 hours. Media was then removed and replaced with
fresh media containing Alamar Blue. The cells were incubated for a
further 4 hours and Alamar blue and conversion was assessed by
fluorescence. Compound effectiveness was determined by assessing
the reduction in Alamar blue bioconversion following 24 hour
treatment.
* * * * *