U.S. patent application number 10/206265 was filed with the patent office on 2004-01-29 for fluorenes and anthracenes that inhibit p2x3 and p2x2/3 containing receptors.
Invention is credited to Bayburt, Erol, Gomtsyan, Arthur, Jiang, Meiqun, Lee, Chih-Hung, Perner, Richard, Zheng, Guo Zhu.
Application Number | 20040019042 10/206265 |
Document ID | / |
Family ID | 30770250 |
Filed Date | 2004-01-29 |
United States Patent
Application |
20040019042 |
Kind Code |
A1 |
Lee, Chih-Hung ; et
al. |
January 29, 2004 |
FLUORENES AND ANTHRACENES THAT INHIBIT P2X3 AND P2X2/3 CONTAINING
RECEPTORS
Abstract
Compounds of formula (I) 1 are novel P2X.sub.3 and
P2X.sub.2/P2X.sub.3 containing receptor antagonists and are useful
in treating pain, urinary incontinence, and bladder
overactivity.
Inventors: |
Lee, Chih-Hung; (Vernon
Hills, IL) ; Jiang, Meiqun; (Gurnee, IL) ;
Perner, Richard; (Gurnee, IL) ; Gomtsyan, Arthur;
(Vernon Hills, IL) ; Bayburt, Erol; (Gurnee,
IL) ; Zheng, Guo Zhu; (Lake Bluff, IL) |
Correspondence
Address: |
STEVEN F. WEINSTOCK
ABBOTT LABORATORIES
100 ABBOTT PARK ROAD
DEPT. 377/AP6A
ABBOTT PARK
IL
60064-6008
US
|
Family ID: |
30770250 |
Appl. No.: |
10/206265 |
Filed: |
July 26, 2002 |
Current U.S.
Class: |
514/224.8 ;
544/37 |
Current CPC
Class: |
C07C 2603/18 20170501;
C07C 311/21 20130101; C07C 2603/24 20170501; C07C 311/29
20130101 |
Class at
Publication: |
514/224.8 ;
544/37 |
International
Class: |
A61K 031/5415; C07D
279/18 |
Claims
What is claimed is:
1. A compound of formula (I) 22or a pharmaceutically acceptable
salt, ester, amide, or prodrug thereof, wherein A.sub.1 and A.sub.2
are independently selected from the group consisting of hydrogen
and 23provided that one of A.sub.1 and A.sub.2 is hydrogen; L.sub.1
and L.sub.2 are independently selected from the group consisting of
N(R.sub.11) and S(O).sub.2, provided that when L.sub.1 is
N(R.sub.11) then L.sub.2 is S(O).sub.2 or when L.sub.1 is
S(O).sub.2 then L.sub.2 is N(R.sub.11); L.sub.3 is selected from
the group consisting of S, S(O), S(O).sub.2, C(O), CH(OR.sub.12),
C(.dbd.NOR.sub.13), C(.dbd.NNR.sub.12R.sub.14),
C(.dbd.CHC(O)OR.sub.12), CH.sub.2, and CH.sub.2CH.sub.2; L.sub.4 is
selected from the group consisting of a covalent bond, C(O),
CH(OR.sub.12), C(.dbd.NOR.sub.13), and C(.dbd.NNR.sub.12R.sub.14);
L.sub.5 and L.sub.6 are independently selected from the group
consisting of N(R.sub.15) and S(O).sub.2, provided that when
L.sub.5 is N(R.sub.15) then L.sub.6 is S(O).sub.2 or when L.sub.5
is S(O).sub.2 then L.sub.6 is N(R.sub.15); R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, and
R.sub.10 are independently selected from the group consisting of
hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl,
alkylcarbonyloxy, halogen, haloalkoxy, haloalkyl, hydroxy, and
--NZ.sub.1Z.sub.2 wherein Z.sub.1 and Z.sub.2 are independently
selected from the group consisting of hydrogen, alkyl, and
alkylcarbonyl; R.sub.11, R.sub.12, R.sub.14, and R.sub.15 are
independently selected from the group consisting of hydrogen and
alkyl; and R.sub.13 is selected from the group consisting of
hydrogen, alkyl, and carboxyalkyl.
2. A compound according to claim 1 wherein A.sub.1 is 24L.sub.1 and
L.sub.5 are --S(O).sub.2--; L.sub.2 is N(R.sub.11); L.sub.6 is
N(R.sub.15); and L.sub.4 is a covalent bond.
3. A compound according to claim 2 wherein R.sub.1, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9, and R.sub.10 are
hydrogen; R.sub.2 and R.sub.7 are independently selected from the
group consisting of hydroxy, alkoxy, and --NZ.sub.1Z.sub.2; and
L.sub.3 is C(O).
4. A compound according to claim 3 selected from the group
consisting of
N,N'-bis(3-hydroxyphenyl)-9-oxo-9H-fluorene-2,7-disulfonamide;
N-(3-{[(7-{[(3-hydroxyphenyl)amino]sulfonyl}-9-oxo-9H-fluoren-2-yl)sulfon-
yl]amino}phenyl)acetamide;
N-(3-aminophenyl)-N'-(3-hydroxyphenyl)-9-oxo-9H-
-fluorene-2,7-disulfonamide; and
N,N'-bis(3-hydroxyphenyl)-N-methyl-9-oxo--
9H-fluorene-2,7-disulfonamide.
5. A compound according to claim 2 wherein R.sub.1, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9, and R.sub.10 are
hydrogen; R.sub.2 and R.sub.7 are independently selected from the
group consisting of hydroxy, alkoxy, and --NZ.sub.1Z.sub.2; and
L.sub.3 is C(.dbd.NOR.sub.13).
6. A compound according to claim 5
9-(hydroxyimino)-N,N'-bis(3-hydroxyphen-
yl)-9H-fluorene-2,7-disulfonamide;
{[(2,7-bis{[(3-hydroxyphenyl)amino]sulf-
onyl}-9H-fluoren-9-ylidene)amino]oxy}acetic acid;
N-(3-{[(9-(hydroxyimino)-
-7-{[(3-hydroxyphenyl)amino]sulfonyl}-9H-fluoren-2-yl)sulfonyl]amino}pheny-
l)acetamide; N-(3
-aminophenyl)-9-(hydroxyimino)-N'-(3-hydroxyphenyl)-9H-f-
luorene-2,7-disulfonamide; and
9-(hydroxyimino)-N,N'-bis(3-hydroxyphenyl)--
N-methyl-9H-fluorene-2,7-disulfonamide.
7. A compound according to claim 2 wherein R.sub.1, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9, and R.sub.10 are
hydrogen; R.sub.2 and R.sub.7 are independently selected from the
group consisting of hydroxy, alkoxy, and --NZ.sub.1Z.sub.2; and
L.sub.3 is C(.dbd.NNR.sub.12R.sub.14).
8. A compound according to claim 7 selected from the group
consisting of
9-hydrazono-N,N'-bis(3-hydroxyphenyl)-9H-fluorene-2,7-disulfonamide;
and
N,N'-bis(3-hydroxyphenyl)-9-(methylhydrazono)-9H-fluorene-2,7-disulfonami-
de.
9. A compound according to claim 2 wherein R.sub.1, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9, and R.sub.10 are
hydrogen; R.sub.2 and R.sub.7 are independently selected from the
group consisting of hydroxy, alkoxy, and --NZ.sub.1Z.sub.2; and
L.sub.3 is CH(OR.sub.12).
10. A compound according to claim 9 that is
9-hydroxy-N,N'-bis(3-hydroxyph-
enyl)-9H-fluorene-2,7-disulfonamide.
11. A compound according to claim 2 wherein R.sub.1, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9, and R.sub.10 are
hydrogen; R.sub.2 and R.sub.7 are independently selected from the
group consisting of hydroxy, alkoxy, and --NZ.sub.1Z.sub.2; and
L.sub.3 is C(.dbd.CHC(O)OR.sub.12).
12. A compound according to claim 11 that is
(2,7-bis{[(3-hydroxyphenyl)am-
ino]sulfonyl}-9H-fluoren-9-ylidene)acetic acid.
13. A compound according to claim 1 wherein A.sub.1 is 25L.sub.1 is
N(R.sub.11); L.sub.5 is N(R.sub.15); L.sub.2 and L.sub.6 are
S(O).sub.2; and L.sub.4 is a covalent bond.
14. A compound according to claim 13 wherein R.sub.1, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9, and R.sub.10 are
hydrogen; R.sub.2 and R.sub.7 are independently selected from the
group consisting of hydroxy, alkoxy, and --NZ.sub.1Z.sub.2; and
L.sub.3 is C(O).
15. A compound according to claim 14 selected from the group
consisting of
3-methoxy-N-(7-{[(3-methoxyphenyl)sulfonyl]amino}-9-oxo-9H-fluoren-2-yl)b-
enzenesulfonamide;
3-hydroxy-N-(7-{[(3-hydroxyphenyl)sulfonyl]amino}-9-oxo-
-9H-fluoren-2-yl)benzenesulfonamide; and
3-hydroxy-N-(9-(hydroxyimino)-7-{-
[(3-hydroxyphenyl)sulfonyl]amino}-9H-fluoren-2-yl)benzenesulfonamide.
16. A compound according to claim 1 wherein A.sub.1 is 26L.sub.1
and L.sub.5 are S(O).sub.2; L.sub.2 is N(R.sub.11); L.sub.6 is
N(R.sub.15); L.sub.3 and L.sub.4 are independently selected from
the group consisting of C(O) and C(.dbd.NOR.sub.13); and R.sub.13
is hydrogen.
17. A compound according to claim 16 wherein R.sub.1, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9, and R.sub.10 are
hydrogen; and R.sub.2 and R.sub.7 are independently selected from
the group consisting of hydroxy, alkoxy, and --NZ.sub.1Z.sub.2.
18. A compound according to claim 17 selected from the group
consisting of
N,N'-bis(3-hydroxyphenyl)-9,10-dioxo-9,10-dihydro-2,7-anthracenedisulfona-
mide;
10-(hydroxyimino)-N,N'-bis(3-hydroxyphenyl)-9-oxo-9,10-dihydro-2,7-a-
nthracenedisulfonamide; and
9,10-bis(hydroxyimino)-N,N'-bis(3-hydroxypheny-
l)-9,10-dihydro-2,7-anthracenedisulfonamide.
19. A compound according to claim 1 wherein A.sub.2 is 27L.sub.1
and L.sub.5 are S(O).sub.2; L.sub.2 is N(R.sub.11); L.sub.6 is
N(R.sub.15); L.sub.3 and L.sub.4 are independently selected from
the group consisting of C(O) and C(.dbd.NOR.sub.13); and R.sub.13
is hydrogen.
20. A compound according to claim 19 wherein R.sub.1, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9, and R.sub.10 are
hydrogen; and R.sub.2 and R.sub.7 are independently selected from
the group consisting of hydroxy, alkoxy, and --NZ.sub.1Z.sub.2.
21. A compound according to claim 20 selected from the group
consisting of
N,N'-bis(3-hydroxyphenyl)-9,10-dioxo-9,10-dihydro-2,6-anthracenedisulfona-
mide;
10-(hydroxyimino)-N,N'-bis(3-hydroxyphenyl)-9-oxo-9,10-dihydro-2,6-a-
nthracenedisulfonamide; and
9,10-bis(hydroxyimino)-N,N'-bis(3-hydroxypheny-
l)-9,10-dihydro-2,6-anthracenedisulfonamide.
22. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof in combination with a pharmaceutically
acceptable carrier.
23. A method of treating bladder overactivity in a mammal in need
of such treatment comprising administering to the mammal a
therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
24. A method of treating urinary incontinence in a mammal in need
of such treatment comprising administering to the mammal a
therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
25. A method of treating pain in a mammal in need of such treatment
comprising administering to the mammal a therapeutically effective
amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to compounds of formula (I),
which are useful for treating diseases or conditions caused by or
exacerbated by P2X receptor activity, pharmaceutical compositions
containing compounds of formula (I) and methods of treatment using
compounds of formula (I).
BACKGROUND OF THE INVENTION
[0002] P2X receptors function as homomultimeric cation-permeable
ion channels and, in some cases, as heteromeric channels consisting
of two different P2X receptor subtypes. At least one pair of P2X
receptor subtypes, P2X.sub.2 and P2X.sub.3, functions as a
heteromeric channel in rat nodose ganglion neurons where it
exhibits distinct pharmacological and electrophysiological
properties.
[0003] With respect to individual receptors, the rat P2X.sub.2
containing receptor is expressed in the spinal cord, and in the
nodose and dorsal root ganglia, while rat P2X.sub.3 containing
receptor expression is found primarily in a subset of neurons of
the sensory ganglia. The distribution of both receptors is
consistent with a role in pain transmission. The P2X.sub.2 and
P2X.sub.3 subunits form functional channels when expressed alone,
and can also form a functional heteromultimeric channel that has
properties similar to currents seen in native sensory channels when
co-expressed. Evidence from studies in rat nodose ganglia indicate
that both P2X.sub.2/P2X.sub.3 heteromeric channels and P2X.sub.2
homomeric channels contribute to adenosine triphosphate-induced
currents.
[0004] ATP, which activates P2X.sub.2, P2X.sub.3, and
P2X.sub.2/P2X.sub.3 containing receptors, functions as an
excitatory neurotransmitter in the spinal cord dorsal horn and in
primary afferents from sensory ganglia. ATP-induced activation of
P2X receptors on dorsal root ganglion nerve terminals in the spinal
cord stimulates the release of glutamate, a key neurotransmitter
involved in nociceptive signaling. Thus, ATP released from damaged
cells can evoke pain by activating P2X.sub.2, P2X.sub.3, or
P2X.sub.2/P2X.sub.3 containing receptors on nociceptive nerve
endings of sensory nerves. This is consistent with the induction of
pain by intradermally applied ATP in the human blister-base model;
the identification of P2X.sub.3 containing receptors on nociceptive
neurons in the tooth pulp; and with reports that P2X antagonists
are analgesic in animal models. This evidence suggests that
P2X.sub.2 and P2X.sub.3 function in nociception, and that
modulators of these human P2X receptors are useful as
analgesics.
[0005] It has been recently demonstrated that P2X.sub.3 receptor
gene disruption results in a diminished sensitivity to noxious
chemical stimuli and reduced pain. P2X.sub.3 containing receptor
knock-out mice also exhibited a marked urinary bladder hyporeflexia
upon cystometric evaluation, suggesting that P2X.sub.3 antagonists
have utility for treating bladder overactivity. P2X.sub.3 knock-out
mice had decreased voiding frequency, increased voiding volume, but
normal bladder pressure. It has been proposed that ATP acts as a
physiological regulator of sensory neurotransmission in visceral
hollow organs such as bladder, and P2X.sub.3 containing receptors
localized on the basal surface of the urothelium. The urology data
on the P2X.sub.3 knock-out mice suggest that P2X.sub.3 plays a
major role in modulating the volume threshold for activation of
micturition and that P2X.sub.3 antagonists have therapeutic utility
for urinary incontinence.
[0006] The nociceptive effects of exogenously administered ATP and
P2X containing receptor agonists have also been demonstrated in
laboratory animals. The peripheral nociceptive actions of P2X
activation and stimulation of spinal P2X containing receptors also
contribute to nociception as indicated by the ability of
intrathecally (i.t.) administered P2 receptor agonists to increase
sensitivity to acute and persistent noxious stimuli in rodents.
[0007] The utility of available purinergic ligands to evaluate the
role of individual P2 receptor subtypes in mammalian physiology has
been complicated by the susceptibility of P2 receptor agonists to
undergo enzymatic degradation, and by the lack of P2 receptor
subtype-selective agonists and antagonists.
[0008] Since subtype-selective ligands for the individual P2
receptors have yet to be identified, efforts to elucidate the
specific P2X containing receptor subtypes involved in the
transmission of nociceptive signals has been largely based on
receptor localization and functional studies using
immunohistochemical techniques. These studies have shown that both
the homomeric P2X.sub.3 and heteromeric P2X.sub.2/3 containing
receptor subtypes are selectively localized to the central and
peripheral terminals of small diameter sensory neurons. Further,
recent data has shown that P2X.sub.3 specific immunoreactivity is
significantly increased in both the injured dorsal root ganglion
and in the ipsalateral spinal dorsal horn following chronic
constriction injury of the rat sciatic nerve.
[0009] The functional and immunohistochemical localization of
P2X.sub.3 and/or P2X.sub.2/3 containing receptors on sensory nerves
indicates that these P2X containing receptors have a primary role
in mediating the nociceptive effects of exogenous ATP. Thus,
compounds which block or inhibit activation of P2X.sub.3 containing
receptors serve to block the pain stimulus. Antagonists of the
P2X.sub.3 homomeric channel and/or the P2X.sub.2/P2X.sub.3
heteromeric channel could successfully block the transmission of
pain.
[0010] The compounds of the present invention are novel P2X.sub.3
and P2X.sub.2/3 antagonists, have utility in treating pain as well
as in treating bladder overactivity and urinary incontinence.
SUMMARY OF THE INVENTION
[0011] The present invention discloses fluorene and anthracene
compounds, a method for controlling pain in mammals, and
pharmaceutical compositions including those compounds. More
particularly, the present invention is directed to compounds of
formula (I) 2
[0012] or a pharmaceutically acceptable salt, ester, amide, or
prodrug thereof, wherein
[0013] A.sub.1 and A.sub.2 are independently selected from hydrogen
or 3
[0014] provided that one of A.sub.1 and A.sub.2 is hydrogen;
[0015] L.sub.1 and L.sub.2 are independently selected from
N(R.sub.11) or S(O).sub.2, provided that when L.sub.1 is
N(R.sub.11) then L.sub.2 is S(O).sub.2 or when L.sub.1 is
S(O).sub.2 then L.sub.2 is N(R.sub.11);
[0016] L.sub.3 is selected from S, S(O), S(O).sub.2, C(O),
CH(OR.sub.12), C(.dbd.NOR.sub.13), C(.dbd.NNR.sub.12R.sub.14),
C(.dbd.CHC(O)OR.sub.12), CH.sub.2, or CH.sub.2CH.sub.2;
[0017] L.sub.4 is selected from a covalent bond, C(O),
CH(OR.sub.12), C(.dbd.NOR.sub.13), or
C(.dbd.NNR.sub.12R.sub.14);
[0018] L.sub.5 and L.sub.6 are independently selected from
N(R.sub.15) or S(O).sub.2, provided that when L.sub.5 is
N(R.sub.15) then L.sub.6 is S(O).sub.2 or when L.sub.5 is
S(O).sub.2 then L.sub.6 is N(R.sub.15);
[0019] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are independently selected
from hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl,
alkylcarbonyl, alkylcarbonyloxy, halogen, haloalkoxy, haloalkyl,
hydroxy, or --NZ.sub.1Z.sub.2 wherein Z.sub.1 and Z.sub.2 are
independently selected from hydrogen, alkyl, or alkylcarbonyl;
[0020] R.sub.11, R.sub.12, R.sub.14, and R.sub.15 are independently
selected from hydrogen and alkyl; and
[0021] R.sub.13 is selected from hydrogen, alkyl, or
carboxyalkyl.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
[0022] All references contained herein are fully incorporated by
reference.
[0023] In the principle embodiment, compounds of formula (I) are
disclosed 4
[0024] or a pharmaceutically acceptable salt, ester, amide, or
prodrug thereof, wherein
[0025] A.sub.1 and A.sub.2 are independently selected from hydrogen
or 5
[0026] provided that one of A.sub.1 and A.sub.2 is hydrogen;
[0027] L.sub.1 and L.sub.2 are independently selected from
N(R.sub.11) or S(O).sub.2, provided that when L.sub.1 is
N(R.sub.11) then L.sub.2 is S(O).sub.2 or when L.sub.1 is
S(O).sub.2 then L.sub.2 is N(R.sub.11);
[0028] L.sub.3 is selected from S, S(O), S(O).sub.2, C(O),
CH(OR.sub.12), C(.dbd.NOR.sub.13), C(.dbd.NNR.sub.12R.sub.14),
C(.dbd.CHC(O)OR.sub.12), CH.sub.2, or CH.sub.2CH.sub.2;
[0029] L.sub.4 is selected from a covalent bond, C(O),
CH(OR.sub.12), C(.dbd.NOR.sub.13), or
C(.dbd.NNR.sub.12R.sub.14);
[0030] L.sub.5 and L.sub.6 are independently selected from
N(R.sub.15) or S(O).sub.2, provided that when L.sub.5 is
N(R.sub.15) then L.sub.6 is S(O).sub.2 or when L.sub.5 is
S(O).sub.2 then L.sub.6 is N(R.sub.15);
[0031] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are independently selected
from hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl,
alkylcarbonyl, alkylcarbonyloxy, halogen, haloalkoxy, haloalkyl,
hydroxy, or --NZ.sub.1Z.sub.2 wherein Z, and Z.sub.2 are
independently selected from hydrogen, alkyl, or alkylcarbonyl;
[0032] R.sub.11, R.sub.12, R.sub.14, and R.sub.15 are independently
selected from hydrogen or alkyl; and
[0033] R.sub.13 is selected from hydrogen, alkyl, or
carboxyalkyl.
[0034] In another embodiment of the present invention, compounds of
formula (I) are disclosed wherein A.sub.2 is hydrogen; A.sub.1 is
6
[0035] L.sub.1 and L.sub.5 are S(O).sub.2; L.sub.2 is N(R.sub.11);
L.sub.4 is a covalent bond; L.sub.6 is N(R.sub.15); and L.sub.3,
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.8, R.sub.9, R.sub.10, R.sub.11, and R.sub.15 are as defined
in formula (I)
[0036] In another embodiment of the present invention, compounds of
formula (I) are disclosed wherein A.sub.2 is hydrogen; A.sub.1 is
7
[0037] L.sub.1 and L.sub.5 are S(O).sub.2; L.sub.2 is N(R.sub.11);
L.sub.4 is a covalent bond; L.sub.6 is N(R.sub.15); R.sub.1,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9, and R.sub.10
are hydrogen; R.sub.2 and R.sub.7 are independently selected from
hydroxy, alkoxy, or --NZ.sub.1Z.sub.2; L.sub.3 is C(O); and
Z.sub.1, Z.sub.2, R.sub.11, and R.sub.15 are as defined in formula
(I).
[0038] In another embodiment of the present invention, compounds of
formula (I) are disclosed wherein A.sub.2 is hydrogen; A.sub.1 is
8
[0039] L.sub.1 and L.sub.5 are S(O).sub.2; L.sub.2 is N(R.sub.11);
L.sub.4 is a covalent bond; L.sub.6 is N(R.sub.15); R.sub.1,
R.sub.3, R.sub.4, R.sub.5 R.sub.6, R.sub.8, R.sub.9, and R.sub.10
are hydrogen; R.sub.2 and R.sub.7 are independently selected from
hydroxy, alkoxy, or --NZ.sub.1Z.sub.2; L.sub.3 is
C(.dbd.NOR.sub.13); and Z.sub.1, Z.sub.2, R.sub.11, R.sub.13, and
R.sub.15 are as defined in formula (I).
[0040] In another embodiment of the present invention, compounds of
formula (I) are disclosed wherein A.sub.2 is hydrogen; A.sub.1 is
9
[0041] L.sub.1 and L.sub.5 are S(O).sub.2; L.sub.2 is N(R.sub.11,);
L.sub.4 is a covalent bond; L.sub.6 is N(R.sub.15); R.sub.1,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9, and R.sub.10
are hydrogen; R.sub.2 and R.sub.7 are independently selected from
hydroxy, alkoxy, or --NZ.sub.1Z.sub.2; L.sub.3 is
C(.dbd.NNR.sub.12R.sub.14); and Z.sub.1, Z.sub.2, R.sub.11,
R.sub.12, R.sub.14, and R.sub.15 are as defined in formula (I).
[0042] In another embodiment of the present invention, compounds of
formula (I) are disclosed wherein A.sub.2 is hydrogen; A.sub.1 is
10
[0043] L.sub.1 and L.sub.5 are S(O).sub.2; L.sub.2 is N(R.sub.11,);
L.sub.4 is a covalent bond; L.sub.6 is N(R.sub.15); R.sub.1,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9, and R.sub.10
are hydrogen; R.sub.2 and R.sub.7 are independently selected from
hydroxy, alkoxy, or --NZ.sub.1Z.sub.2; L.sub.3 is CH(OR.sub.12);
and Z.sub.1, Z.sub.2, R.sub.11, R.sub.12, and R.sub.15 are as
defined in formula (I).
[0044] In another embodiment of the present invention, compounds of
formula (I) are disclosed wherein A.sub.2 is hydrogen; A.sub.1 is
11
[0045] L.sub.1 and L.sub.5 are S(O).sub.2; L.sub.2 is N(R.sub.11);
L.sub.4 is a covalent bond; L.sub.6 is N(R.sub.15); R.sub.1,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9, and R.sub.10
are hydrogen; R.sub.2 and R.sub.7 are independently selected from
hydroxy, alkoxy, or --NZ.sub.1Z.sub.2; L.sub.3 is
C(.dbd.CHC(O)OR.sub.12); and Z.sub.1, Z.sub.2, R.sub.11, R.sub.12,
and R.sub.15 are as defined in formula (I).
[0046] In another embodiment of the present invention, compounds of
formula (I) are disclosed wherein A.sub.2 is hydrogen; A.sub.1 is
12
[0047] L.sub.1 is N(R.sub.11); L.sub.5 is N(R.sub.15); L.sub.2 and
L.sub.6 are --S(O).sub.2; L.sub.4 is a covalent bond; and L.sub.3,
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.8, R.sub.9, R.sub.10, R.sub.11, and R.sub.15 are as defined
in formula (I).
[0048] In another embodiment of the present invention, compounds of
formula (I) are disclosed wherein A.sub.2 is hydrogen; A.sub.1 is
13
[0049] L.sub.1 is N(R.sub.11,); L.sub.5 is N(R.sub.15); L.sub.2 and
L.sub.6 are --S(O).sub.2; L.sub.4 is a covalent bond; R.sub.1,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9, and R.sub.10
are hydrogen; R.sub.2 and R.sub.7 are independently selected from
hydroxy, alkoxy, or --NZ.sub.1Z.sub.2; L.sub.3 is C(O); and
Z.sub.1, Z.sub.2, R.sub.11, and R.sub.15 are as defined in formula
(I).
[0050] In another embodiment of the present invention, compounds of
formula (I) are disclosed wherein A.sub.2 is hydrogen; A.sub.1 is
14
[0051] L.sub.1 and L.sub.5 are S(O).sub.2; L.sub.2 is N(R.sub.11);
L.sub.6 is N(R.sub.15); L.sub.3 and L.sub.4 are independently
selected from C(O) or C(.dbd.NOR.sub.13); R.sub.13 is hydrogen; and
R.sub.1, R.sub.2, R.sub.3, R.sub.4,R.sub.5, R.sub.6, R.sub.7,
R.sub.8, R.sub.9, R.sub.10, R.sub.11, and R.sub.15 are as defined
in formula (I).
[0052] In another embodiment of the present invention, compounds of
formula (I) are disclosed wherein A.sub.2 is hydrogen; A.sub.1 is
15
[0053] L.sub.1 and L.sub.5 are S(O).sub.2; L.sub.2 is N(R.sub.11);
L.sub.6 is N(R.sub.15); L.sub.3 and L.sub.4 are independently
selected from C(O) or C(.dbd.NOR.sub.13); R.sub.13 is hydrogen;
R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9, and
R.sub.10 are hydrogen; R.sub.2 and R.sub.7 are independently
selected from hydroxy, alkoxy, or --NZ.sub.1Z.sub.2; and Z.sub.1,
Z.sub.2, R.sub.11, and R.sub.15 are as defined in formula (I).
[0054] In another embodiment of the present invention, compounds of
formula (I) are disclosed wherein A.sub.1 is hydrogen; A.sub.2 is
16
[0055] L.sub.1 and L.sub.5 are S(O).sub.2; L.sub.2 is N(R.sub.11);
L.sub.6 is N(R.sub.15); L.sub.3 and L.sub.4 are independently
selected from C(O) or C(.dbd.NOR.sub.13); R.sub.13 is hydrogen; and
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.8, R.sub.9, R.sub.10, R.sub.11, and R.sub.15 are as defined
in formula (I).
[0056] In another embodiment of the present invention, compounds of
formula (I) are disclosed wherein A.sub.1 is hydrogen; A.sub.2 is
17
[0057] L.sub.1 and L.sub.5 are S(O).sub.2; L.sub.2 is N(R.sub.11);
L.sub.6 is N(R.sub.15); L.sub.3 and L.sub.4 are independently
selected from C(O) or C(.dbd.NOR.sub.13); R.sub.13 is hydrogen;
R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9, and
R.sub.10 are hydrogen; R.sub.2 and R.sub.7 are independently
selected from hydroxy, alkoxy, or --NZ.sub.1Z.sub.2; and Z.sub.1,
Z.sub.2, R.sub.11, and R.sub.15 are as defined in formula (I).
[0058] Another embodiment of the present invention relates to
pharmaceutical compositions comprising a therapeutically effective
amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof in combination with a pharmaceutically
acceptable carrier.
[0059] Another embodiment of the present invention relates to a
method for treating pain in a mammal in need of such treatment
comprising administering to the mammal a therapeutically effective
amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof in combination with a pharmaceutically
acceptable carrier.
[0060] Another embodiment of the present invention relates to a
method of treating urinary incontinence in a mammal in need of such
treatment comprising administering a therapeutically effective
amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof.
[0061] Another embodiment of the present invention relates to a
method of treating bladder overactivity in a mammal in need of such
treatment comprising administering a therapeutically effective
amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof.
[0062] Definition of Terms
[0063] As used throughout this specification and the appended
claims, the following terms have the following meanings:
[0064] The term "alkenyl" as used herein, means a straight or
branched chain hydrocarbon containing from 2 to 10 carbons and
containing at least one carbon-carbon double bond formed by the
removal of two hydrogens. Representative examples of alkenyl
include, but are not limited to, ethenyl, 2-propenyl,
2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,
2-methyl-1-heptenyl, and 3-decenyl.
[0065] The term "alkoxy" as used herein, means an alkyl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Representative examples of alkoxy include, but are not
limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,
tert-butoxy, pentyloxy, and hexyloxy.
[0066] The term "alkoxycarbonyl" as used herein, means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkoxycarbonyl include, but are not limited to,
methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
[0067] The term "alkoxycarbonylalkyl" as used herein, means an
alkoxycarbonyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of alkoxycarbonylalkyl include, but are not
limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and
2-tert-butoxycarbonylethyl.
[0068] The term "alkyl" as used herein, means a straight or
branched chain hydrocarbon containing from 1 to 10 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,
and n-decyl.
[0069] The term "alkylcarbonyl" as used herein, means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkylcarbonyl include, but are not limited to, acetyl,
1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and
1-oxopentyl.
[0070] The term "alkylcarbonyloxy" as used herein, means an
alkylcarbonyl group, as defined herein, appended to the parent
molecular moiety through an oxygen atom. Representative examples of
alkylcarbonyloxy include, but are not limited to, acetyloxy,
ethylcarbonyloxy, and tert-butylcarbonyloxy.
[0071] The term "carbonyl" as used herein, means a --C(O)--
group.
[0072] The term "carboxy" as used herein, means a --CO.sub.2H
group.
[0073] The term "carboxyalkyl" as used herein, means a carboxy
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of carboxyalkyl include, but are not limited to, carboxymethyl,
2-carboxyethyl, and 3-carboxypropyl.
[0074] The term "halo" or "halogen" as used herein, means --Cl,
--Br, --I or --F.
[0075] The term "haloalkoxy" as used herein, means at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkoxy group, as defined herein. Representative examples
of haloalkoxy include, but are not limited to, chloromethoxy,
2-fluoroethoxy, trifluoromethoxy, 2-chloro-3-fluoropentyloxy, and
pentafluoroethoxy.
[0076] The term "haloalkyl" as used herein, means at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of haloalkyl include, but are not limited to, chloromethyl,
2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and
2-chloro-3-fluoropentyl.
[0077] The term "hydroxy" as used herein, means an --OH group.
[0078] Compounds of the present invention were named by
ACD/ChemSketch version 5.0 (developed by Advanced Chemistry
Development, Inc., Toronto, ON, Canada) or were given names which
appeared to be consistent with ACD nomenclature.
[0079] Representative compounds of the present invention include,
but are not limited to:
[0080]
9-(hydroxyimino)-N,N'-bis(3-hydroxyphenyl)-9H-fluorene-2,7-disulfon-
amde;
[0081] {[(2,7-bis
{[(3-hydroxyphenyl)amino]sulfonyl}-9H-fluoren-9-ylidene)-
amino]oxy}acetic acid;
[0082]
9-hydroxy-N,N'-bis(3-hydroxyphenyl)-9H-fluorene-2,7-disulfonamide;
[0083]
9-hydrazono-N,N'-bis(3-hydroxyphenyl)-9H-fluorene-2,7-disulfonamide-
;
[0084] (2,7-bis
{[(3-hydroxyphenyl)amino]sulfonyl}-9H-fluoren-9-ylidene)ac- etic
acid;
[0085]
N-(3-{[(9-(hydroxyimino)-7-{[(3-hydroxyphenyl)amino]sulfonyl}-9H-fl-
uoren-2-yl)sulfonyl]amino}phenyl)acetamide;
[0086]
N-(3-aminophenyl)-9-(hydroxyimino)-N'-(3-hydroxyphenyl)-9H-fluorene-
-2,7-disulfonamide;
[0087]
9-(hydroxyimino)-N,N'-bis(3-hydroxyphenyl)-N-methyl-9H-fluorene-2,7-
-disulfonamide;
[0088]
N,N'-bis(3-hydroxyphenyl)-9-(methylhydrazono)-9H-fluorene-2,7-disul-
fonamide;
[0089]
N,N'-bis(3-hydroxyphenyl)-9,10-dioxo-9,10-dihydro-2,7-anthracenedis-
ulfonamide;
[0090]
10-(hydroxyimino)-N,N'-bis(3-hydroxyphenyl)-9-oxo-9,10-dihydro-2,7--
anthracenedisulfonamide;
[0091]
9,10-bis(hydroxyimino)-N,N'-bis(3-hydroxyphenyl)-9,10-dihydro-2,7-a-
nthracenedisulfonamide;
[0092]
N,N'-bis(3-hydroxyphenyl)-9,10-dioxo-9,10-dihydro-2,6-anthracenedis-
ulfonamide;
[0093]
10-(hydroxyimino)-N,N'-bis(3-hydroxyphenyl)-9-oxo-9,10-dihydro-2,6--
anthracenedisulfonamide;
[0094]
9,10-bis(hydroxyimino)-N,N'-bis(3-hydroxyphenyl)-9,10-dihydro-2,6-a-
nthracenedisulfonamide;
[0095]
3-methoxy-N-(7-{[(3-methoxyphenyl)sulfonyl]amino}-9-oxo-9H-fluoren--
2-yl)benzenesulfonamide;
[0096] 3-hydroxy-N-(7-{[(3-hydroxyphenyl)sulfonyl]amino
}-9-oxo-9H-fluoren-2-yl)benzenesulfonamide; and
[0097]
3-hydroxy-N-(9-(hydroxyimino)-7-{[(3-hydroxyphenyl)sulfonyl]amino}--
9H-fluoren-2-yl)benzenesulfonamide; or pharmaceutically acceptable
salts, amides, esters, or prodrugs thereof.
[0098] Abbreviations
[0099] Abbreviations which have been used in the descriptions of
the Schemes and the Examples that follow are: DMSO for
dimethylsulfoxide; HPLC high pressure liquid chromatography; and
THF for tetrahydrofuran.
[0100] Preparation of Compounds of the Present Invention
[0101] The compounds and processes of the present invention will be
better understood in connection with the following synthetic
Schemes and Examples which illustrate a means by which the
compounds of the present invention can be prepared. 18
[0102] Fluorenes of general formula (3), wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.9, R.sub.10,
R.sub.11, and R.sub.15 are as defined in formula (I), can be
prepared as described in Scheme 1. 9-Oxo-9H-fluorene-2,7-disulfonyl
dichloride, purchased from Maybridge, can be treated with anilines
of general formula (1) and (2) to provide fluorenes of general
formula (3). 19
[0103] Fluorenes of general formula (5), (7), and (9), wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14,
and R.sub.15 are as defined in formula (I), can be prepared as
described in Scheme 2. Fluorenes of general formula (3) can be
treated with amines of general formula (4) and a catalytic amount
of acid in an alcoholic solvent such as, but not limited to,
ethanol with heat to provide fluorenes of general formula (5).
[0104] Fluorenes of general formula (3) can be treated with
hydrazines of general formula (6) and a catalytic amount of acid in
an alcoholic solvent such as, but not limited to, ethanol with heat
to provide fluorenes of general formula (7).
[0105] Fluorenes of general formula (3) can be treated with
phosphonium reagents of general formula (8) under standard Wittig
conditions to provide fluorenes of general formula (9). Fluorenes
of general formula (3) can also be treated with phosphonates under
standard Homer-Wadsworth-Emmons conditions to provide fluorenes of
general formula (9). 20
[0106] Fluorenes of general formula (14), wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, P.sub.6, R.sub.7, R.sub.8, R.sub.9,
R.sub.10, R.sub.11, and R.sub.15 are as defined in formula (I), can
be prepared as described in Scheme 3. Fluorenes of general formula
(11), prepared as described in P. J. Perry, M. A. Read, R. T.
Davies, S. M. Gowan, A. P. Reszka, A. A. Wood, L. R. Kelland, S.
Neidle, J. Med. Chem. 1999, 42, 2679, can be treated with sulfonyl
chlorides of general formula (12) and (13) in a solvent or
cosolvent such as, but not limited to, THF and pyridine to provide
fluorenes of general formula (14). 21
[0107] Anthracenes of general formula (16), wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8,
R.sub.9, and R.sub.10 are as defined in formula (I), can be
prepared as described in Scheme 4. Anthraquinone-2,7-disulfonic
acid disodium salt, can be treated with phosphorous oxychloride to
provide anthracenedisulfonyl dichloride. Anthracenedisulfonyl
dichloride can be treated with anilines of general formula (1) and
(2) to provide anthracenes of general formula (16).
[0108] Anthraquinone-2,6-disulfonic acid disodium salt can be
treated as described in Scheme 4 to provide 2,6-disubstituted
anthracenes.
[0109] Anthracenes of general formula (16) can be treated as
described in Scheme 2 to provide oximes, hydrazones, .alpha.,.beta.
unsaturated esters, or .alpha.,.beta. unsaturated acids.
[0110] The following Examples are intended as an illustration of
and not a limitation upon the scope of the invention as defined in
the appended claims.
EXAMPLE 1
9-(hydroxyimino)-N,N'-bis(3-hydroxyphenyl)-9H-fluorene-2,7-disulfonamide
EXAMPLE 1A
N,N'-bis(3-hydroxyphenyl)-9-oxo-9H-fluorene-2,7-disulfonamide
[0111] 3-Aminophenol (0.91 g, 8.38 mmol) in pyridine was treated
with 9-oxo-9H-fluorene-2,7-disulfonyl dichloride (1.58 g, 4.19
mmol, purchased from Maybridge) in one portion at 0.degree. C.
After two hours, the volatiles were removed at reduced pressure and
the residue was partitioned between ethyl acetate and H.sub.2O. The
organic layer was separated, washed with 1N HCl, brine, dried
(Na.sub.2SO.sub.4), filtered, and the filtrate concentrated under
reduced pressure. The residue was purified by flash chromatography
(8% CH.sub.3OH/CH.sub.2Cl.sub.2) to provide the title compound as a
yellow solid (1.97 g, 90% yield). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 10.31 (s, 2H), 9.50 (s, 2H), 7.97-8.11 (m,
4H), 7.92 (d, 2H), 7.0 (t, 2H), 6.49-6.64 (m, 4H), 6.43 (m, 2H); MS
(DCI/NH.sub.3) 540 (M+NH.sub.4).sup.+.
EXAMPLE 1B
9-(hydroxyimino)-N,N'-bis(3-hydroxyphenyl)-9H-fluorene-2,7-disulfonamide
[0112] The product from Example 1A (1.35 g, 2.58 mmol) in absolute
ethanol (20 ML) was treated with hydroxylamine hydrochloride (0.20
g, 2.84 mmol) and two drops of concentrated HCl and heated at
reflux for 5 hours. The mixture was allowed to cool to room
temperature and concentrated under reduced pressure. The residue
was dissolved in ethyl acetate, washed with saturated NaHCO.sub.3
solution, brine, dried (Na.sub.2SO.sub.4), filtered, and the
filtrate was concentrated under reduced pressure. The residue was
solidified by addition of 5% CH.sub.3OH/CH.sub.2Cl.sub.2 then
collected by filtration and dried under reduced pressure to provide
the title compound as a white solid (0.92 g, 66% yield). .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 13.29 (bs, 1H), 10.21 (m, 2H),
9.40 (m, 2H), 8.75 (m, 1H), 8.02-8.15 (m, 3H), 7.80-7.90 (m, 2H),
6.96 (m, 2H), 6.57 (m, 2H), 6.52 (m, 2H), 6.40 (m, 2H); MS (ESI)
536 (M-H).sup.-; Anal calcd for
C.sub.25H.sub.19N.sub.3O.sub.7S.sub.2: C, 55.86; H, 3.56; N, 7.82.
Found: C, 55.64; H, 3.71; N, 7.61.
EXAMPLE 2
{[(2,7-bis{[(3-hydroxyphenyl)amino]sulfonyl}-9H-fluoren-9-ylidene)amino]ox-
y}acetic acid
[0113] The product from Example 1A in pyridine (3 mL) was treated
with carboxymethoxylamine hemihydrochloride (93 mg, 0.43 mmol) and
heated at reflux. After 30 minutes, the solution was allowed to
cool to ambient temperature and the volatiles were removed at
reduced pressure. The residue was partitioned between ethyl acetate
and concentrated NH.sub.4Cl. The organic layer was separated,
washed with brine, dried (Na.sub.2SO.sub.4), filtered, and the
filtrate concentrated under reduced pressure. The residue was
triturated with CH.sub.2Cl.sub.2, collected by filtration, and
dried under reduced pressure to provide the title compound as a
white solid (128 mg, 56% yield). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta.10.1-10.4 (bs, 2H), 9.4-9.6 (bs, 1H),8.95 (m,
1H), 8.02-8.17 (m, 3H), 7.93 (m, 1H), 7.80 (m, 1H), 6.90-7.02 (m,
2H), 6.82 (m, 1H), 6.27-6.58 (m, 5H), 4.74 (s, 2H); MS (ESI) 594
(M-H).sup.-.
EXAMPLE 3
9-hydroxy-N,N'-bis(3-hydroxyphenyl)-9H-fluorene-2,7-disulfonamide
[0114] The product from Example 1A (213 mg, 0.41 mmol) in absolute
ethanol (5 mL) at 0.degree. C. was treated cautiously with
NaBH.sub.4 (46 mg, 1.22mmol). After 2 hours, the mixture was
quenched with 1N HCl and diluted with ethyl acetate. The organic
layer was separated, washed with saturated NaHCO.sub.3 solution,
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated under
reduced pressure to provide the title compound as a white solid
(154 mg, 72% m yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta.10.22 (s, 2H), 9.43 (s, 2H), 7.95-8.05 (m, 4H), 7.80 (dd,
2H), 6.96 (t, 2H), 6.5-6.61 (m, 4H), 6.39 (m, 2H), 6.26 (d, 1H),
5.61 (d, 1H); MS (ESI) 523 (M-H).sup.-.
EXAMPLE 4
9-hydrazono-N,N'-bis(3
-hydroxyphenyl)-9H-fluorene-2,7-disulfonamide
EXAMPLE 4A
tert-butyl
2-(2,7-bis{[(3-hydroxyphenyl)amino]sulfonyl}-9H-fluoren-9-ylide-
ne)hydrazinecarboxylate
[0115] The product from Example 1A (317 mg, 0.60 mmol) in ethanol
(10 mL) was treated with H.sub.2NNHBoc (87 mg, 0.66 mmol) and a
catalytic amount of p-toluenesulfonic acid. The mixture was heated
at reflux for 3 hours, allowed to cool to room temperature, and
concentrated under reduced pressure. The residue was purified by
flash chromatography eluting with 8% CH.sub.3OH/CH.sub.2Cl.sub.2 to
provide the title compound as a yellow solid (241 mg, 63% yield).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.11.29 (bs, 1H), 10.28
(bs, 2H), 9.45 (d, 2H), 8.52 (bs, 1H), 8.04-8.18 (m, 3H), 7.87 (m,
1H), 7.81 (m, 1H), 6.98 (m, 2H), 6.5-6.6 (m, 4H), 6.4 (m, 2H), 1.59
(s, 9H); MS (ESI) 635 (M-H).sup.-.
EXAMPLE 4B
9-hydrazono-N,N'-bis(3-hydroxyphenyl)-9H-fluorene-2,7-disulfonamide
[0116] The product from Example 4A (218 mg, 0.34 mmol) in absolute
ethanol was treated with three crystals of p-toluenesulfonic acid
and heated at reflux. After 3 hours, the mixture was allowed to
cool to room temperature and was concentrated under reduced
pressure. The residue was taken up in ethyl acetate, washed with
saturated NaHCO.sub.3 solution, brine, dried (Na.sub.2SO.sub.4),
filtered, and the filtrate was concentrated under reduced pressure.
The residue was purified by flash chromatography (85% ethyl
acetate/hexanes) to provide the title compound as a yellow solid
(36 mg, 20% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
9.41 (d, 2H), 8.78 (bs, 2H), 8.63 (bs, 1H), 8.28 (d, 1H), 8.02-8.1
(m, 2H), 7.81 (dd, 1H), 7.70 (dd, 1H), 6.91-7.01 (m, 2H), 6.49-6.61
(m, 4H), 6.33-6.42 (m, 2H); MS (ESI) 535 (M-H).sup.-.
EXAMPLE 5
(2,7-bis{[(3-hydroxyphenyl)amino]sulfonyl}-9H-fluoren-9-ylidene)acetic
acid
EXAMPLE 5A
ethyl
(2,7-bis{[(3-hydroxyphenyl)amino]sulfonyl}-9H-fluoren-9-ylidene)acet-
ate
[0117] (Carbethoxymethyl)triphenyl-phosphonium bromide (3.73 g,
8.69 mmol) in dry 1,4-dioxane was treated with potassium
tert-butoxide (0.98 g, 8.69 mmol). After stirring for 90 minues,
the mixture was treated with the product from Example 1A (0.83 g,
1.58 mmol). After stirring for 5 hours, the mixture was treated
with water and extracted with ethyl acetate. The organic phase was
separated, washed with brine, dried (Na.sub.2SO.sub.4), filtered,
and the filtrate concentrated under reduced pressure. The residue
was purified by flash chromatography (70% ethyl acetate/hexanes) to
provide the title compound (0.47 g, 50% yield). .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta.9.44 (d, 2H), 9.18 (d, 1H), 8.44 (d, 1H),
8.10 (m, 2H), 7.87 (m, 2H), 7.23 (m, 1H), 6.98 (m, 2H), 6.5-6.63
(m, 4H), 6.39 (m, 2H), 4.35 (q, 2H), 1.35 (t, 3H); MS (ESI) 591
(M-H).sup.-.
EXAMPLE 5B
(2,7-bis{[(3-hydroxylhenyl)amino]sulfonyl}-9H-fluoren-9-ylidene)acetic
acid
[0118] The product from Example 5A (460 mg, 0.78 mmol) in THF (5
mL) and 15% aqueous NaOH (5 mL) was heated at reflux for 6 hours.
The mixture was allowed to cool to ambient temperature, acidified,
and extracted with ethyl acetate. The organic phase was separated,
washed with brine, dried (Na.sub.2SO.sub.4), filtered, and the
filtrate concentrated under reduced pressure to provide the title
compound as a yellow solid (95 mg, 22% yield). .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta.10.26 (s, 1H), 10.16 (s, 1H), 9.43 (s,
1H), 9.18 (d, 1H), 8.37 (d, 1H), 8.1 (m, 2H), 7.86 (m, 2H), 7.2 (s,
1H), 7.0 (t, 2H), 6.53-6.63(m, 4H), 6.42 (m, 2H). MS (ESI) 563
(M-H).sup.-.
EXAMPLE 6
N-(3
-{[(9-(hydroxyimino)-7-{[(3-hydroxyphenyl)amino]sulfonyl}-9H-fluoren--
2-yl)sulfonyl]amino}phenyl)acetamide
EXAMPLE 6A
N-(3
-{[(7-{[(3-hydroxyphenyl)amino]sulfonyl}-9-oxo-9H-fluoren-2-yl)sulfon-
yl]amino}phenyl)acetamide
[0119] 3-Aminophenol (0.29 g, 2.65 mmol) and
N-(3-aminophenyl)acetamide (0.49 g, 2.65 mmol) in pyridine were
treated with 9-oxo-9H-fluorene-2,7-d- isulfonyl dichloride (1.00 g,
2.65 mmol) in one portion at 0 .degree. C. The mixture was allowed
to warm to ambient temperature and stirred for 1 hour after which
the volatiles were evaporated under reduced pressure. The residue
was partitioned between ethyl acetate and H.sub.2O. The separated
organic phase was washed with 1N HCl, brine, dried
(Na.sub.2SO.sub.4), filtered, and the filtrate concentrated under
reduced pressure. The residue was purified by flash chromatography
(85% ethyl acetate/hexanes) to provide the title compound as a
yellow solid (577 mg, 39% yield). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta.9.91 (bs, 1H), 9.47 (s, 1H), 7.9-8.1 (m, 6H),
7.48 (m, 1H), 7.26 bd, 1H), 7.12 (t, 1H), 6.99 (t, 1H), 6.75 (m,
1H), 6.58 (t, 1H), 6.52 (dd, 1H), 6.42 (dd, 1H), 1.98 (s, 3H); MS
(ESI) 562 (M-H).sup.-.
EXAMPLE 6B
N-(3-{[(9-(hydroxyimino)-7-{[(3-hydroxyphenyl)amino]sulfonyl}-9H-fluoren-2-
-yl)sulfonyl]amino}phenyl)acetamide
[0120] The product from Example 6A (223 mg, 0.396 mmol) in pyridine
(3 mL) was treated with hydroxylamine hydrochloride (30 mg, 0.435
mmol) and heated at reflux. After 30 minutes, the mixture was
allowed to cool to ambient temperature and partitioned between
ethyl acetate and H.sub.2O. The separated organic phase was washed
with 1 N HCl, brine, dried (Na.sub.2SO.sub.4), filtered, and the
filtrate concentrated under reduced pressure. The residue was
purified by flash chromatography (75% ethyl acetate/hexanes) to
provide the title compound as a light yellow solid (91 mg, 40%
yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.13.32 (bs, 1H),
10.2-10.4 (bs, 2H), 9.89 (s, 1H), 9.43 (d, 1H), 8.75 (m, 1H),
8.03-8.17 (m, 3H), 7.8-7.95 (m, 2H), 7.45 (m, 1H), 7.25 (m, 1H),
7.1 (m, 1H), 6.98 (m, 1H), 6.75 (m, 1H), 6.58 (m, 1H), 6.52 (m,
1H), 6.4 (m, 1H), 1.98 (s, 3H); MS (ESI) 577 (M-H).sup.-.
EXAMPLE 7
N-(3-aminophenyl)-9-(hydroxyimino)-N'-(3-hydroxyphenyl)-9H-fluorene-2,7-di-
sulfonamide
EXAMPLE 7A
N-(3-aminophenyl)-N'-(3
-hydroxyphenyl)-9-oxo-9H-fluorene-2,7-disulfonamid- e
[0121] The product from Example 6A (289 mg, 0.554 mmol) in THF:MeOH
(1:1, 20 mL) and 15% aq NaOH (10 mL) was heated at reflux. After 24
hours, the volatiles were evaporated at reduced pressure and the
residue was partitioned between ethyl acetate and saturated
NaHCO.sub.3. The separated aqueous phase was extracted with ethyl
acetate. The combined organic extracts were washed with brine,
dried (Na.sub.2SO.sub.4), filtered, and the filtrate concentrated
under reduced pressure. The residue was purified by flash
chromatography (80% ethyl acetate/hexanes) to provide the title
compound as an orange solid (172 mg, 55% yield). .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta.9.50 (1H), 7.97-8.1 (m, 4H), 7.92 (d,
2H), 7.00 (t, 1H), 6.83 (t, 1H), 6.58 (t, 1H), 6.53 (m, 1H), 6.42
(m, 1H), 6.35 (t, 1H), 6.22 (m, 2H), 5.14 (bs, 2H). MS (ESI) 520
(M-H).sup.-.
EXAMPLE 7B
N-(3-aminophenyl)-9-(hydroxyimino)-N'-(3-hydroxyphenyl)-9H-fluorene-2,7-di-
sulfonamide
[0122] The product from Example 7A (134 mg, 0.257 mmol) in pyridine
(3 mL) was treated with hydroxylamine hydrochloride (20 mg, 0.283
mmol) and stirred at ambient temperature. After 3 hours, the
mixture was partitioned between ethyl acetate and 1N HCl. The
separated organic phase was washed with 1N HCl, saturated
NaHCO.sub.3, brine, dried (Na.sub.2SO.sub.4), filtered, and the
filtrate concentrated under reduced pressure. The residue was
dissolved in a minimum amount of ethyl acetate and CH.sub.2Cl.sub.2
was added to effect precipitation. The solid was collected by
filtration and dried under reduced pressure to provide the title
compound as a white solid (123 mg, 89% yield). .sup.1H NMR (300
MHz, DMSO-d,.sub.6) .delta.13.43 (bs, 1H), 10.17-10.35 (m, 1H),
9.96-10.13 (m, 1H), 9.46 (d, 1H), 8.76 (d, 1H), 8.02-8.18 (m, 3H),
7.8-7.93 (m, 2H), 6.98 (m, 1H), 6.81 (m, 1H), 6.5-6.6 (m, 2H),
6.32-6.44 (m, 2H), 6.16-6.28 (m, 2H), 5.1 (bs, 2H); MS (ESI) 535
(M-H).sup.-.
EXAMPLE 8
9-(hydroxyimino)-N,N'-bis(3
-hydroxyphenyl)-N-methyl-9H-fluorene-2,7-disul- fonamide
EXAMPLE 8A
3 -(methylamino)phenol
[0123] 3-Aminophenol (5.37 g, 49.2 mmol) in ethylformate (30 mL)
was treated with p-toluenesulfonic acid (50 mg) and heated at
reflux. After 18 hours, the volatiles were evaporated under reduced
pressure. The residue was taken up in ethyl acetate and washed with
1N HCl , saturated NaHCO.sub.3, brine, dried (Na.sub.2SO.sub.4),
filtered, and the filtrate concentrated under reduced pressure. The
residue was dissolved in THF (25 mL) and treated with 1M borane
tetrahydofuran complex (27.2 mL, 27.2 mmol) in THF. After 18 hours
at ambient temperature, the mixture was carefully quenched by
additon of 1N HCl. After stirring for 30 minutes, the solution was
basified and extracted with ethyl acetate. The organic layer was
separated, washed with brine, dried (Na.sub.2SO.sub.4), filtered,
and the filtrate concentrated under reduced pressure. The residue
was purified by flash chromatography (30% ethyl acetate/hexanes) to
provide the title compound as a viscous yellow oil (1.72 g, 28%
yield). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.03 (t, 1H),
6.13-6.24 (m, 2H), 6.11 (t, 1H), 4.54 (bs, 1H), 3.72 (bs, 1H), 2.82
(s, 3H); MS (DCI/NH.sub.3) 124 (M+H).sup.+, 141
(M.sup.+NH.sub.4).sup.+.
EXAMPLE 8B
N,N'-bis(3-hydroxyphenyl)-N-methyl-9-oxo-9H-fluorene-2,7-disulfonamide
[0124] The product from Example 8A and 3-aminophenol were processed
as described in Example 6A to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta.10.29 (bs, 1H), 9.58 (bs, 1H),
9.48 (bs, 1H), 8.12 (m, 2H), 8.04 (dd, 1H), 7.95 (d, 1H), 7.80 (dd,
1H), 7.58 (d, 1H), 7.11 (t, 1H), 7.01 (t, 1H), 6.71 (m, 1H), 6.60
(t, 1H), 6.49-6.58 (m, 3H), 6.44 (m, 1H), 3.13 (s, 3H); MS (ESI)
535 (M-H).sup.-.
EXAMPLE 8C
9-(hydroxyimino)-N,N'-bis(3
-hydroxyphenyl)-N-methyl-9H-fluorene-2,7-disul- fonamide
[0125] The product from Example 8B was processed as described in
Example 7B to provide the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta.9.58 (s, 1H), 9.47 (d, 1H), 7.62-8.78 (m, 6H),
7.1 (m, 1H), 6.99 (m, 1H), 6.68 (m, 1H), 6.47-6.62 (m, 4H), 6.41
(m, 1H), 3.11 (s, 3H); MS (ESI) 550 (M-H).sup.-.
EXAMPLE 9
N,N'-bis(3-hydroxyphenyl)-9-(methylhydrazono)-9H-fluorene-2,7-disulfonamid-
e
[0126] The product from Example 1A (0.5 g, 0.94 mmol) in EtOH (5
mL) was treated with methylhydrazine (0.06 mL, 1.1 mmol), and a
catalytic amount of TsOH. The mixture was refluxed for 3 hours,
allowed to cool to room temperature, concentrated under reduced
pressure, and the residue was purified by flash chromatography
(CH.sub.2Cl.sub.2:MeOH, 98:2) to provide the title compound as a
yellow foam (0.3 g, 58% yield).
[0127] .sup.1H-NMR (DMSO-d.sub.6) .delta.10.15 (broad s, 2H), 9.40
(d, J=6Hz, 2H), 8.85 (d, 3.5 Hz, 1H), 8.60 (d, J=0.5 Hz, 1H), 8.18
(d, J=7.5 Hz, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.72-7.63 (m, 2H), 6.95
(m, 2H), 6.60-6.50 (m, 4H), 6.38 (m, 2H), 3.32 (s, 3H); MS (APCI)
m/z 551 (M+H).sup.+.
EXAMPLE 10
N,N'-bis(3-hydroxyphenyl)-9,10-dioxo-9,10-dihydro-2,7-anthracenedisulfonam-
ide
EXAMPLE 10A
9,10-dioxo-9,10-dihydro-2,7-anthracenedisulfonyl dichloride
[0128] Anthraquinone-2,7-disulfonic acid disodium salt (1.24 g, 3
mmol) and sulfolane (5 ml) in acetonitrile (5 ml) was treated with
phosphorous oxychloride (2.3 ml, 25 mmol). The mixture was heated
at reflux for 20 hours, allowed to cool to room temperature, and
filtered through a pad of silica gel with methylene chloride. The
filtrate was concentrated under reduced pressure and the crude
product was used in the next step without further purification.
EXAMPLE 10B
[0129]
N,N'-bis(3-hydroxyphenyl)-9,10-dioxo-9,10-dihydro-2,7-anthracenedis-
ulfonamide
[0130] 3-aminophenol (0.76 g, 7 mmol) in pyridine (10 ml) was
treated with the product from Example 10A in methylene chloride.
The mixture was stirred at room temperature for 18 hours and the
solvents removed under reduced pressure. The residue was taken up
in ethyl acetate, washed three times with 1N hydrochloric acid,
dried with magnesium sulfate, filtered, and the filtrate
concentrated under reduced pressure. The residue was filtered
through a pad of silica gel with 5% methanol in methylene chloride.
The filtrate was concentrated under reduced pressure and the
residue was taken up in a mixture of ethyl acetate:hexanes (1:1).
The mixture was washed three times with water, dried with magnesium
sulfate, filtered, and the filtrate concentrated under reduced
pressure. The residue was titurated with methylene chloride and the
orange solid collected by filtration to provide the title compound
(0.47 g, 28% yield for 2 steps). .sup.1H NMR (CD.sub.3OD)
.delta.7.16 (d, 2H, J=1.5 Hz), 6.86 (d, 2H, J=6 Hz), 6.69 (dd, 2H,
J.sub.1=6 Hz, J.sub.2=1.5 Hz), 5.55-5.47 (m, 2H), 5.20-4.95 (m,
6H); MS (ESI-) 549 (M-H).sup.-.
EXAMPLE 11
10-(hydroxyimino)-N,N'-bis(3-hydroxyphenyl)-9-oxo-9,10-dihydro-2,7-anthrac-
enedisulfonamide
[0131] The product from Example 10B (110 mg, 0.2 mmol) and
hydroxylamine hydrochloride (0.69 g, 10 mmol) were dissolved in
methanol (6 ml) and heated at reflux for 18 hours. The mixture was
allowed to cool to room temperature and the methanol was removed
under reduced pressure. The residue was taken up in water,
extracted with 10% methanol in methylene chloride, the aqueous
layer was brought to pH 7 with aqueous sodium bicarbonate, and
extracted again with ethyl acetate. All the organic layers were
combined, dried with magnesium sulfate, filtered, and the filtrate
concentrated under reduced pressure. The residue was purified by
flash chromatography eluting with 5% methanol in methylene
chloride, followed by preperative thin-layer chromatography eluting
with 10% methanol in methylene chloride to provide the title
compound (20 mg, 18% yield) and the bis(oxime) (28 mg, 24% yield).
.sup.1H NMR (CD.sub.3OD) .delta.9.37 (d, 1H, J=7 Hz), 8.73 (d, 1H,
J=2 Hz), 8.61 (d, 1H, J=2 Hz), 8.41 (d, 1H, J=7 Hz), 8.08 (dd, 1H,
J.sub.1=7 Hz, J.sub.2=2 Hz), 7.96 (dd, 1H, J.sub.1=7 Hz, J.sub.2=2
Hz), 7.00-6.95 (m, 2H), 6.63 (narrow m, 2H), 8.10-8.05 (m, 2H),
7.98-7.94 (m, 2H); MS (ESI+) 566 (M+H).sup.+.
EXAMPLE 12
9,10-bis(hydroxyimino)-N,N'-bis(3-hydroxyphenyl)-9,10-dihydro-2,7-anthrace-
nedisulfonamide
[0132] The title compound was isolated as one of the products from
Example 11. .sup.1H NMR (CD.sub.3OD) .delta.9.24 and 9.19 (2d, 1H,
J=2 Hz), 8.83 and 8.75 (2d, 1H, J=6 Hz), 8.44 and 8.35 (2d, 1H, J=2
Hz), 8.07 and 7.97 (2d, 1H, J=7 Hz), 7.87-7.69 (m, 2H)7.02-6.94 (m,
2H), 6.66-6.44 (m, 6H); MS (ESI+) 581 (M+H).sup.+.
EXAMPLE 13
N,N'-bis(3-hydroxyphenyl)-9,10-dioxo-9,10-dihydro-2,6-anthracenedisulfonam-
ide
EXAMPLE 13A
9,10-dioxo-9,10-dihydro-2,6-anthracenedisulfonyl dichloride
[0133] Anthraquinone-2,6-disulfonic acid disodium salt was
processed as described in Example 10A to provide the title
compound.
EXAMPLE 13B
N,N'-bis(3-hydroxyphenyl)-9,10-dioxo-9,10-dihydro-2,6-anthracenedisulfonam-
ide
[0134] The product from Example 13A was processed as described in
Example 10B to provide the title compound. .sup.1H NMR (CD.sub.3OD)
8.49 (d, 2H, J=1 Hz), 8.23 (d, 2H, J=6 Hz), 8.05 (dd, 2H, J.sub.1=6
Hz, J.sub.2=1 Hz), 6.90-6.81 (m, 2H), 6.54-6.30 (m, 6H); MS (ESI-)
549 (M-H).sup.-.
EXAMPLE 14
10-(hydroxyimino)-N,N'-bis(3-hydroxyphenyl)-9-oxo-9,10-dihydro-2,6-anthrac-
enedisulfonamide
[0135] The product from Example 13B was processed as described in
Example 11 to provide the title compound. .sup.1H NMR (CD.sub.3OD)
.delta.9.68 and 8.58 (2d, 1H, J=3Hz), 9.32 and 8.27 (2d, 1H, J=8
Hz), 8.73 and 8.71 (2d, 1H, J=3 Hz), 8.42 and 8.39 (2d, 8.10 and
7.89 (2dd, 1H, J.sub.1=8 Hz, J.sub.2=3 Hz), 8.01 and 7.97 (2dd, 1H,
J.sub.1=9 Hz, J.sub.2=3 Hz), 7.02-6.97 (m, 2H), 6.66-6.62 (m, 2H),
6.59-6.53 (m, 2H), 6.50-6.45 (m, 2H); MS (ESI-) 564
(M-H).sup.-.
EXAMPLE 15
9,10-bis(hydroxyimino)-N,N'-bis(3-hydroxyphenyl)-9,10-dihydro-2,6-anthrace-
nedisulfonamide
[0136] The product from Example 13B was processed as described in
Example 11 to provide the title compound. .sup.1H NMR (CD.sub.3OD)
9.21, 9.17, 8.33, 8,42 (4d, 2H, J=2 Hz), 8.85, 8.78, 8.09, 7.98
(4d, 2H, J=6 Hz), 7.85, 7.78, 7.72 (3dd, 2H, J.sub.1=2 Hz,
J.sub.2=6 Hz), 7.01-6.95 (m, 2H), 6.65-6.61 (m, 2H), 6.57-6.45 (m,
4H); MS (ESI+) 581 (M+H).sup.+.
EXAMPLE 16
3-methoxy-N-(7-{[(3
-methoxyphenyl)sulfonyl]amino}-9-oxo-9H-fluoren-2-yl)b-
enzenesulfonamide
EXAMPLE 16A
2,7-diamino-9H-fluoren-9-one
[0137] The title compound was prepared according to the procedure
described in P. J. Perry, M. A. Read, R. T. Davies, S. M. Gowan, A.
P. Reszka, A. A. Wood, L. R. Kelland, S. Neidle, J. Med. Chem.
1999, 42, 2679.
EXAMPLE 16B
3-methoxy-N-(7-{[(3-methoxyphenyl)sulfonyl]amino}-9-oxo-9H-fluoren-2-yl)be-
nzenesulfonamide
[0138] 3-Methoxybenzenesulfonyl chloride (4.75 g, 23.0 mmol) in THF
(40 mL) was treated with the product from Example 16A (5.05 g, 24
mmol) in THF (60 ML) and pyridine (60 mL) over 10 minutes. After an
additional 30 minutes, the mixture was quenched with a mixture of
1.0M (pH 6) aqueous potassium phosphate buffer (30 mL) and brine
(20 mL). The aqueous phase was separated and extracted with diethyl
ether. The organic phases were combined, washed 1.0M (pH 6) aqueous
potassium phosphate buffer (10 mL) and brine (10 mL), and the
aqueous phase was extracted with diethyl ether. All the organic
phases were combined, dried (Na.sub.2SO.sub.4), concentrated, and
the filtrate concentrated under reduced pressure. The residue was
purified by flash chromatography (ethyl acetate/CH.sub.2Cl.sub.2).
The appropriate fractions were concentrated, dissolved in a small
quantity of hot methanol and triturated with diethyl ether. The
resulting precipitate was collected by filtration and washed with
(10% methanol/diethyl ether) to provide the title compound as an
orange powder (3.51 g). 1H HNMR (DMSO-d.sub.6) .delta.10.55 (bs, 2
H), 7.53 (d, J=8.5 Hz, 2 H), 7.47 (t, J=8.0 Hz, 2 H), 7.33 (d,
J=7.6 Hz, 2 H), 7.28-7.24 (m, 6 H), 7.18 (dd, J=8.5, 2.1, 2 H),
3.77 (s, 6 H); MS calculated for (M+H): 550.0868; observed:
550.0848; IR 3232, 2971, 1719, 1599, 1466, 1256, 1155.
EXAMPLE 17
3-hydroxy-N-(7-{[(3-hydroxyphenyl)sulfonyl]amino}-9-oxo-9H-fluoren-2-yl)be-
nzenesulfonamide
[0139] The product from Example 16 (551 mg, 1.00 mmol) in
CH.sub.2Cl.sub.2 was treated with BBr.sub.3 (.about.475 .mu.L, 5.0
mmol). After 2.5 hours, additional BBr.sub.3 (.about.235 .mu.L, 2.5
mmol) was added to the mixture. After an additional 40 minutes, the
mixture was poured onto ice-cold 0.3M (pH 6) aqueous potassium
phosphate buffer (100 mL), diluted with ethyl acetate (100 mL). The
organic phase was separated, dried (Na.sub.2SO.sub.4),
concentrated, filtered, and the filtrate was slurried in
CH.sub.2Cl.sub.2 to provide a precipitate which was twice
chromatographed (CH.sub.3CN/CH.sub.2Cl.sub.2) to provide the title
compound as an orange powder (327 mg). .sup.1H HNMR (CD.sub.3OD)
.delta.7.35-7.27 (m, 6 H), 7.24 (dt, J=7.6, 1.3), 7.19-7.16 (m, 4
H), 6.97 (ddd, J=7.9, 2.5, 1.3, 2 H); MS calculated for (M+H):
522.0555; observed: 522.0560; IR 3457, 3346, 3232, 1718, 1604,
1468, 1311, 1150.
EXAMPLE 18
[0140]
3-hydroxy-N-(9-(hydroxyimino)-7-{[(3-hydroxyphenyl)sulfonyl]amino}--
9H-fluoren-2-yl)benzenesulfonamide
[0141] The product from Example 17 was processed according to the
procedurue described in S. Witek, J. Bielawski, A. Bielawska, Pol.
J. Chem. 1981, 55, 2589, to provide the title compound. .sup.1H NMR
(CD.sub.3OD/CDCl.sub.3) .delta.8.08 (d, J=2.4, 1 H), 7.39 (d,
J=2.0, 1 H), 7.38 (d, J=8.1, 1 H), 7.35 (d, J=8.1, 1 H), 7.25-7.20
(m, 6 H), 7.17 (dd, J=8.1, 2.0, 1 H), 7.11 (dd, J=8.1, 2.0, 1 H),
6.97-6.93 (m, 2 H); MS calculated for (M+H): 537.0664; observed:
537.0671; IR 3397,3260, 1702, 1589, 1464, 1307, 1154.
In Vitro Data
Determination of Inhibition Potencies
[0142] Compounds of the present invention were determined to be
P2X.sub.3 and P2X.sub.2/3 antagonists based on their ability to
inhibit increases in cytosolic Ca.sup.2+ concentration elicited by
the P2X receptor agonist .alpha..beta.-methyleneATP
(.alpha..beta.-meATP; Sigma, St. Louis, Mo.) as described in
Bianchi et al. (1999). The fluorescent Ca.sup.2+ chelating dye
fluo-4 was used as an indicator of the relative levels of
intracellular Ca.sup.2+ in a 96-well format using a Fluorescence
Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, Calif.).
Cells expressing recombinant human P2X.sub.3 or P2X.sub.2/3
containing receptors were grown to confluence and plated in 96-well
black-walled tissue culture plates approximately 18 hours prior to
the experiment. One to two hours before the assay, cells were
loaded with fluo-4 AM (2.28 .mu.M; Molecular Probes, Eugene, Oreg.)
in D-PBS and maintained in a dark environment at room temperature.
Immediately before the assay, each plate was washed twice with 250
.mu.l D-PBS per well to remove extracellular fluo-4 AM and then 100
.mu.l D-PBS was added to the wells. Two 50 .mu.l additions of
compounds (4.times. concentration prepared in D-PBS) were made to
the cells during each experiment. The first addition consisting of
test antagonist was made and incubation continued for 3 minutes
before the addition of the agonist .alpha..beta.-meATP, measurement
continued for 3 minutes after this final addition. Fluorescence
data was collected at 1 or 5 second intervals throughout the course
of each experiment and were analyzed based on the peak increase in
relative fluorescence units compared with basal fluorescence.
Antagonist concentration-response data, expressed as a percentage
of the maximal .alpha..beta.-meATP response in the absence of test
antagonist, were analyzed using GraphPad Prism (San Diego,
Calif.).
[0143] The compounds of the present invention were found to be
antagonists of the P2X.sub.3 containing receptor with potencies
from 5000 nM to 10 nM. In a preferred embodiment, the compounds of
the present invention antagonized P2X.sub.3 containing receptors
with potencies of less than 1000 nM. In a more preferred
embodiment, the compounds of the present invention antagonized
P2X.sub.3 containing receptors with potencies of less than 500
nM.
[0144] Additionally, the compounds of the present invention were
found to be antagonists of the P2X.sub.2/3 containing receptors
with potencies from 5000 nM to 10 nM. In a preferred range, the
compounds of the present invention antagonized P2X.sub.2/3
containing receptors with potencies from 1000 nM to 10 nM. In a
more preferred range, the compounds of the present invention
antagonized P2X.sub.2/3 containing receptors with potencies from
500 nM to 10 nM.
In Vivo Data
Determination of Antinociceptive Effect
[0145] Following a 30-mininute acclimation period to individual
clear observation cages, 50 .mu.l of a 5% formalin solution was
injected subcutaneously (s.c.) into the dorsal aspect of the right
hindpaw of rats (male Sprague-Dawley, 200-300 g) were then returned
to the observation cages, which were suspended above mirrors. Rats,
six per group, were observed for either a continuous period of 60
minutes or for periods of time corresponding to phase 1 and phase 2
of the formalin test (Abbott et al., Pain, 60 (1995) 91-102). Phase
1 of the formalin test was defined as the period of time
immediately following injection of formalin until 10 minutes after
the formalin injection. Effects on Phase 2 of the formalin test
were determined by monitoring for the 20 minute period of time from
30 to 50 minutes following formalin injection. Nociceptive
behaviors were recorded from animals during the session by
observing each animal for one 60 second observation period during
each 5 minute interval. Nociceptive behaviors recorded included
flinching, licking or biting the injected paw.
[0146] The compounds of the present invention were found to have
antinociceptive effects with potencies from 300 .mu.mol/kg to 15
.mu.mol/kg.
[0147] The in vitro and in vivo data demonstrates that compounds of
the present invention antagonize the P2X.sub.3 containing receptor,
antagonize the P2X.sub.2/3 containing receptor, and are useful for
treating pain. Compounds of the present invention are thus useful
for ameliorating or preventing additional disorders that are
affected by the P2X.sub.3 and/or the P2X.sub.2/3 containing
receptors such as bladder overactivity and urinary
incontinence.
[0148] The compounds of the invention, including but not limited to
those specified in the examples, are P2X.sub.3 and
P2X.sub.2/P2X.sub.3 containing receptor antagonists in mammals. As
P2X.sub.3 and P2X.sub.2/P2X.sub.3 containing receptor antagonists,
the compounds of the present invention are useful for the treatment
and prevention of disorders such as bladder overactivity, urinary
incontinence or pain.
[0149] The ability of the compounds of the present invention,
including but not limited to those specified in the examples, to
treat bladder overactivity or urinary incontinence is demonstrated
by Namasivayam et al., Brit. J. Urol. Int. 84L 854-860. (1999).
[0150] The ability of the compounds of the present invention,
including but not limited to those specified in the examples, to
treat pain is demonstrated by Cesare et al., Drug Dev. Res. 50:
S01-02 (2000); Cockayne et al., Drug Dev. Res. 50: 005 (2000);
Bleehen, Br. J. Pharmacol. 62:573-577 (1978); Cook et al., Nature
387:505-508 (1997); and Driessen and Starke, Naunyn Schmiedebergs
Arch. Pharmacol. 350:618-625 (1994).
[0151] The present invention also provides pharmaceutical
compositions that comprise compounds of the present invention. The
pharmaceutical compositions comprise compounds of the present
invention formulated together with one or more non-toxic
pharmaceutically acceptable carriers. The pharmaceutical
compositions can be specially formulated for oral administration in
solid or liquid form, for parenteral injection or for rectal
administration.
[0152] The pharmaceutical compositions of this invention can be
administered to humans and other mammals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments or drops), bucally or as an
oral or nasal spray. The term "parenterally," as used herein,
refers to modes of administration which include intravenous,
intramuscular, intraperitoneal, intrasternal, subcutaneous and
intraarticular injection and infusion.
[0153] The term "pharmaceutically acceptable carrier," as used
herein, means a non-toxic, inert solid, semi-solid or liquid
filler, diluent, encapsulating material or formulation auxiliary of
any type. Some examples of materials which can serve as
pharmaceutically acceptable carriers are sugars such as, but not
limited to, lactose, glucose and sucrose; starches such as, but not
limited to, corn starch and potato starch; cellulose and its
derivatives such as, but not limited to, sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; excipients such as, but not
limited to, cocoa butter and suppository waxes; oils such as, but
not limited to, peanut oil, cottonseed oil, safflower oil, sesame
oil, olive oil, corn oil and soybean oil; glycols; such a propylene
glycol; esters such as, but not limited to, ethyl oleate and ethyl
laurate; agar; buffering agents such as, but not limited to,
magnesium hydroxide and aluminum hydroxide; alginic acid;
pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as, but not limited to, sodium lauryl
sulfate and magnesium stearate, as well as coloring agents,
releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of the
formulator.
[0154] Pharmaceutical compositions of this invention for parenteral
injection comprise pharmaceutically acceptable sterile aqueous or
nonaqueous solutions, dispersions, suspensions or emulsions as well
as sterile powders for reconstitution into sterile injectable
solutions or dispersions just prior to use. Examples of suitable
aqueous and nonaqueous carriers, diluents, solvents or vehicles
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol and the like), vegetable oils (such as
olive oil), injectable organic esters (such as ethyl oleate) and
suitable mixtures thereof. Proper fluidity can be maintained, for
example, by the use of coating materials such as lecithin, by the
maintenance of the required particle size in the case of
dispersions and by the use of surfactants.
[0155] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms can be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid and the
like. It may also be desirable to include isotonic agents such as
sugars, sodium chloride and the like. Prolonged absorption of the
injectable pharmaceutical form can be brought about by the
inclusion of agents which delay absorption such as aluminum
monostearate and gelatin.
[0156] In some cases, in order to prolong the effect of the drug,
it is desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This can be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug then depends upon its rate of dissolution which, in turn, may
depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally administered drug form is
accomplished by dissolving or suspending the drug in an oil
vehicle.
[0157] Injectable depot forms are made by forming microencapsule
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides). Depot
injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[0158] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0159] Solid dosage forms for oral administration include capsules,
tablets, pills, powders and granules. In such solid dosage forms,
the active compound may be mixed with at least one inert,
pharmaceutically acceptable excipient or carrier, such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol and silicic acid;
b) binders such as carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidone, sucrose and acacia; c) humectants such as
glycerol; d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates and sodium carbonate; e) solution retarding agents such
as paraffin; f) absorption accelerators such as quaternary ammonium
compounds; g) wetting agents such as cetyl alcohol and glycerol
monostearate; h) absorbents such as kaolin and bentonite clay and
i) lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate and mixtures
thereof. In the case of capsules, tablets and pills, the dosage
form may also comprise buffering agents.
[0160] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
carriers as lactose or milk sugar as well as high molecular weight
polyethylene glycols and the like.
[0161] The solid dosage forms of tablets, dragees, capsules, pills
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well-known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and may also be of a composition such that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions which can be used
include polymeric substances and waxes.
[0162] The active compounds can also be in micro-encapsulated form,
if appropriate, with one or more of the above-mentioned
carriers.
[0163] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid
dosage forms may contain inert diluents commonly used in the art
such as, for example, water or other solvents, solubilizing agents
and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan and mixtures thereof.
[0164] Besides inert diluents, the oral compositions may also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring and perfuming agents.
[0165] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, tragacanth and mixtures thereof.
[0166] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating carriers
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at room temperature but liquid at
body temperature and therefore melt in the rectum or vaginal cavity
and release the active compound.
[0167] Compounds of the present invention can also be administered
in the form of liposomes. As is known in the art, liposomes are
generally derived from phospholipids or other lipid substances.
Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals which are dispersed in an aqueous medium. Any non-toxic,
physiologically acceptable and metabolizable lipid capable of
forming liposomes can be used. The present compositions in liposome
form can contain, in addition to a compound of the present
invention, stabilizers, preservatives, excipients and the like. The
preferred lipids are natural and synthetic phospholipids and
phosphatidyl cholines (lecithins) used separately or together.
[0168] Methods to form liposomes are known in the art. See, for
example, Prescott, Ed., Methods in Cell Biology, Volume XIV,
Academic Press, New York, N.Y. (1976), p. 33 et seq.
[0169] Dosage forms for topical administration of a compound of
this invention include powders, sprays, ointments and inhalants.
The active compound may be mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants which may be required. Opthalmic
formulations, eye ointments, powders and solutions are also
contemplated as being within the scope of this invention.
[0170] Actual dosage levels of active ingredients in the
pharmaceutical compositions of this invention can be varied so as
to obtain an amount of the active compound(s) which is effective to
achieve the desired therapeutic response for a particular patient,
compositions and mode of administration. The selected dosage level
will depend upon the activity of the particular compound, the route
of administration, the severity of the condition being treated and
the condition and prior medical history of the patient being
treated.
[0171] When used in the above or other treatments, a
therapeutically effective amount of one of the compounds of the
present invention can be employed in pure form or, where such forms
exist, in pharmaceutically acceptable salt, ester or prodrug form.
The phrase "therapeutically effective amount" of the compound of
the invention means a sufficient amount of the compound to treat
disorders, at a reasonable benefit/risk ratio applicable to any
medical treatment. It will be understood, however, that the total
daily usage of the compounds and compositions of the present
invention will be decided by the attending physician within the
scope of sound medical judgement. The specific therapeutically
effective dose level for any particular patient will depend upon a
variety of factors including the disorder being treated and the
severity of the disorder; activity of the specific compound
employed; the specific composition employed; the age, body weight,
general health, sex and diet of the patient; the time of
administration, route of administration, and rate of excretion of
the specific compound employed; the duration of the treatment;
drugs used in combination or coincidental with the specific
compound employed; and like factors well known in the medical
arts.
[0172] The compounds of the present invention can be used in the
form of pharmaceutically acceptable salts derived from inorganic or
organic acids. The phrase "pharmaceutically acceptable salt" means
those salts which are, within the scope of sound medical judgement,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response and
the like and are commensurate with a reasonable benefit/risk
ratio.
[0173] Pharmaceutically acceptable salts are well-known in the art.
For example, S. M. Berge et al. describe pharmaceutically
acceptable salts in detail in (J. Pharmaceutical Sciences, 1977,
66: 1 et seq). The salts can be prepared in situ during the final
isolation and purification of the compounds of the invention or
separately by reacting a free base function with a suitable organic
acid. Representative acid addition salts include, but are not
limited to acetate, adipate, alginate, citrate, aspartate,
benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate,
maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,
oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate,
picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
phosphate, glutamate, bicarbonate, p-toluenesulfonate and
undecanoate. Also, the basic nitrogen-containing groups can be
quaternized with such agents as lower alkyl halides such as, but
not limited to, methyl, ethyl, propyl, and butyl chlorides,
bromides and iodides; dialkyl sulfates like dimethyl, diethyl,
dibutyl and diamyl sulfates; long chain halides such as, but not
limited to, decyl, lauryl, myristyl and stearyl chlorides, bromides
and iodides; arylalkyl halides like benzyl and phenethyl bromides
and others. Water or oil-soluble or dispersible products are
thereby obtained. Examples of acids which can be employed to form
pharmaceutically acceptable acid addition salts include such
inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric
acid, and phosphoric acid and such organic acids as acetic acid,
fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic
acid and citric acid.
[0174] Basic addition salts can be prepared in situ during the
final isolation and purification of compounds of this invention by
reacting a carboxylic acid-containing moiety with a suitable base
such as, but not limited to, the hydroxide, carbonate or
bicarbonate of a pharmaceutically acceptable metal cation or with
ammonia or an organic primary, secondary or tertiary amine.
Pharmaceutically acceptable salts include, but are not limited to,
cations based on alkali metals or alkaline earth metals such as,
but not limited to, lithium, sodium, potassium, calcium, magnesium
and aluminum salts and the like and nontoxic quaternary ammonia and
amine cations including ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, diethylamine, ethylamine and the like. Other
representative organic amines useful for the formation of base
addition salts include ethylenediamine, ethanolamine,
diethanolamine, piperidine, piperazine and the like.
[0175] The term "pharmaceutically acceptable prodrug" or "prodrug,"
as used herein, represents those prodrugs of the compounds of the
present invention which are, within the scope of sound medical
judgement, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response, and the like, commensurate with a reasonable benefit/risk
ratio, and effective for their intended use. Prodrugs of the
present invention may be rapidly transformed in vivo to compounds
of formula (I), for example, by hydrolysis in blood.
[0176] The present invention contemplates compounds of formula I
formed by synthetic means or formed by in vivo
biotransformation.
[0177] The compounds of the invention can exist in unsolvated as
well as solvated forms, including hydrated forms, such as
hemi-hydrates. In general, the solvated forms, with
pharmaceutically acceptable solvents such as water and ethanol
among others are equivalent to the unsolvated forms for the
purposes of the invention.
[0178] The total daily dose of the compounds of this invention
administered to a human or lower animal may range from about 0.01
to about 100 mg/kg/day. For purposes of oral administration, more
preferable doses can be in the range of from about 0.1 to about 25
mg/kg/day. If desired, the effective daily dose can be divided into
multiple doses for purposes of administration; consequently, single
dose compositions may contain such amounts or submultiples thereof
to make up the daily dose.
[0179] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
Various changes and modifications to the disclosed embodiments will
be apparent to those skilled in the art. Such changes and
modifications, including without limitation those relating to the
chemical structures, substituents, derivatives, intermediates,
syntheses, formulations and/or methods of use of the invention, may
be made without departing from the spirit and scope thereof.
* * * * *