Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-05-10
2004-12-14
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S041000, C564S123000, C564S161000, C514S408000
Reexamination Certificate
active
06831193
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 ((Lewis et al., Nature 377:432-435 (1995); Le et al., The Journal of Neuroscience, 18 (1998) 7152-7159, Torres et al., Molecular Pharmacology, 54 (1998) 989-993). 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 (Lewis et al., Nature 377:432-435 1995).
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 (Brake et al., Nature 371:519-523 (1994)), while rat P2X
3
containing receptor expression is found primarily in a subset of neurons of the sensory ganglia (Chen et al., Nature 377:428-430 (1995); Vulchanova et al., Neuropharmacol. 36:1229-1242 (1997)). 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 (Lewis et al., Nature 377:432-435 (1995)). 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 (Virginio et al., J Physiol (Lond) 510:27-35 (1998); Thomas et al., J Physiol (Lond) 509 (Pt 2):411-417 (1998)); Vulchanova et al., Proc Natl Acad Sci U S A 93:8063-8067 (1996);; Simon et al., Mol Pharmacol 52:237-248 (1997)).
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 (Holton and Holton, J. Physiol. (Lond.) 126:124-140 (1954)). 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 (Gu and MacDermott, Nature 389:749-753 (1997)). 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 (Bleehen, Br J Pharmacol 62:573-577 (1978)); the identification of P2X
3
containing receptors on nociceptive neurons in the tooth pulp (Cook et al., Nature 387:505-508 (1997)); and with reports that P2X antagonists are analgesic in animal models (Driessen and Starke, Naunyn Schmiedebergs Arch Pharmacol 350:618-625 (1994)). 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 (Cesare et al., Drug Dev. Res. 50: S01-02 (2000); Cockayne et al., Drug Dev. Res. 50: 005 (2000)). 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 (Namasivayam et al., Brit. J. Urol. Int. 84L 854-860. (1999), 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 (Bland-Ward and Humphrey, 1997; Hamilton et al., 1999). 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 (Driessen et al., 1994; Tsuda et al., 1999a; 1999b).
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 (King et al., 1999; Ralevic and Burnstock, 1998).
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 (Chen et al., 1995; Lewis et al., 1995; Vulchanova et al., 1997; 1998). 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 (Novakovic et al., 1999).
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, having utility in treating pain as well as in treating bladder overactivity and urinary incontinence.
SUMMARY OF THE INVENTION
The present invention discloses trisubstituted-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]benzamides 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 pharmaceutically acceptable salts or prodrugs thereof, wherein
A
1
and A
2
are each independently selected from alkoxycarbonyl, alkylcarbonyloxy, carboxy, hydroxy, hydroxyalkyl, (NR
A
R
B
)carbonyl, (NR
C
S(O)
2
R
D
)carbonyl, —S(O)
2
OH, or tetrazolyl; or
A
1
and A
2
together with the carbon atoms to which they are attached form a five membered heterocycle containing a sulfur atom wherein the five membered heterocycle is optionally substituted with 1 or 2 substituents selected from mercapto or oxo;
A
3
is selected from alkoxycarbonyl, alkylcarbonyloxy, carboxy, hydroxy, hydroxyalkyl, (NR
A
R
B
)carbonyl, (NR
C
S(O)
2
R
D
)carbonyl, —S(O)
2
OH, or tetrazolyl;
A
4
, A
5
, A
6
and A
7
are each independently selected from hydrogen, alkoxy, alkoxycarbonyl, alkenyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkynyl, aryl, carboxy, cyano, haloalkoxy, haloalkyl, halogen, heterocycle, hydroxy, hydroxyalkyl, nitro, —NR
E
R
F
, or (NR
E
R
F
)carbonyl;
A
8
Bayburt Erol K.
DiDomenico Stanley
Gomtsyan Arthur R.
Koenig John R.
Larson Daniel P.
Abbott Laboratories
Corbin Johanna M.
Reyes Hector M.
Rotman Alan L.
Ward Michael J.
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