Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2002-07-26
2004-02-17
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S437000, C514S443000, C514S562000, C514S602000, C549S026000, C549S027000, C549S043000, C549S044000, C549S045000, C549S046000, C549S047000, C549S048000, C562S427000, C564S081000, C564S082000, C564S083000
Reexamination Certificate
active
06693136
ABSTRACT:
TECHNICAL FIELD
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
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
2
and P2X
3
, functions as a heteromeric channel in rat nodose ganglion neurons where it exhibits distinct pharmacological and electrophysiological properties.
With respect to individual receptors, the rat P2X
2
containing receptor is expressed in the spinal cord, and in the nodose and dorsal root ganglia, while rat P2X
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
2
and P2X
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
2
/P2X
3
heteromeric channels and P2X
2
homomeric channels contribute to adenosine triphosphate-induced currents.
ATP, which activates P2X
2
, P2X
3
, and P2X
2
/P2X
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
2
, P2X
3
, or P2X
2
/P2X
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
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
2
and P2X
3
function in nociception, and that modulators of these human P2X receptors are useful as analgesics.
It has been recently demonstrated that P2X
3
receptor gene disruption results in a diminished sensitivity to noxious chemical stimuli and reduced pain. P2X
3
containing receptor knock-out mice also exhibited a marked urinary bladder hyporeflexia upon cystometric evaluation, suggesting that P2X
3
antagonists have utility for treating bladder overactivity. P2X
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
3
containing receptors localized on the basal surface of the urothelium. The urology data on the P2X
3
knock-out mice suggest that P2X
3
plays a major role in modulating the volume threshold for activation of micturition and that P2X
3
antagonists have therapeutic utility for urinary incontinence.
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.
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.
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
3
and heteromeric P2X
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
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.
The functional and immunohistochemical localization of P2X
3
and/or P2X
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
3
containing receptors serve to block the pain stimulus. Antagonists of the P2X
3
homomeric channel and/or the P2X
2
/P2X
3
heteromeric channel could successfully block the transmission of pain.
The compounds of the present invention are novel P2X
3
and P2X
2/3
antagonists, have utility in treating pain as well as in treating bladder overactivity and urinary incontinence.
SUMMARY OF THE INVENTION
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)
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein
A
1
and A
2
are independently selected from hydrogen or
provided that one of A
1
and A
2
is hydrogen;
L
1
and L
2
are independently selected from N(R
11
) or S(O)
2
, provided that when L
1
is N(R
11
) then L
2
is S(O)
2
or when L
1
is S(O)
2
then L
2
is N(R
11
);
L
3
is selected from S, S(O), S(O)
2
, C(O), CH(OR
12
), C(═NOR
13
), C(═NNR
12
R
14
), C(═CHC(O)OR
12
), CH
2
, or CH
2
CH
2
;
L
4
is selected from a covalent bond, C(O), CH(OR
12
), C(═NOR
13
), or C(═NNR
12
R
14
);
L
5
and L
6
are independently selected from N(R
15
) or S(O)
2
, provided that when L
5
is N(R
15
) then L
6
is S(O)
2
or when L
5
is S(O)
2
then L
6
is N(R
15
);
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, and R
10
are independently selected from hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, halogen, haloalkoxy, haloalkyl, hydroxy, or —NZ
1
Z
2
wherein Z
1
and Z
2
are independently selected from hydrogen, alkyl, or alkylcarbonyl;
R
11
, R
12
, R
14
, and R
15
are independently selected from hydrogen and alkyl; and
R
13
is selected from hydrogen, alkyl, or carboxyalkyl.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
All references contained herein are fully incorporated by reference.
In the principle embodiment, compounds of formula (I) are disclosed
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein
A
1
and A
2
are independently selected from hydrogen or
provided that one of A
1
and A
2
is hydrogen;
L
1
and L
2
are independently selected from N(R
11
) or S(O)
2
, provided that when L
1
is N(R
11
) then L
2
is S(O)
2
or when L
1
is S(O)
2
then L
2
is N(R
11
);
L
3
is selected from S, S(O), S(O)
2
, C(O), CH(OR
12
), C(═NOR
13
), C(═NNR
12
R
14
), C(═CHC(O)OR
12
), CH
2
, or CH
2
CH
2
;
L
4
is selected from a covalent bond, C(O), CH(OR
12
), C(═NOR
13
), or C(═NNR
12
R
14
);
L
5
and L
6
are independently selected from N(R
15
) or S(O)
2
, provided that when L
5
is N(R
15
) then L
6
is S(O)
2
or when L
5
is S(O)
2
then L
6
is N(R
15
);
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, and R
10
are independently selected from hydrogen, alkenyl
Bayburt Erol K.
Gomtsyan Arthur
Jiang Meiqun
Lee Chih-Hung
Perner Richard A.
Abbott Laboratories
Corbin Johanna M.
O'Sullivan Peter
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