Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-15
2002-11-05
Henley, III, Raymond (Department: 1014)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06476044
ABSTRACT:
BACKGROUND AND SUMMARY OF THE INVENTION
The present invention relates to the use of morphinan derivatives as well as their bases or salts of physiologically compatible acids as regulators for the nociceptin/orphanin FQ ligand ORL1 receptor system and for the production of a medicament.
The heptadecapeptide nociceptin/orphanin FQ is an endogenous ligand of the ORL1 (opioid receptor-like) receptor (Meunier et al., Nature 377, 1995, pp. 532-535) that belongs to the family of opioid receptors and can be found in many regions of the brain and spinal cord (Mollereau et al., FEBS Letters, 341, 1994, pp. 33-38, Darland et al., Trends in Neurosciences, 21, 1998, pp. 215-221). The peptide is characterised by a high affinity, with a Kd value of around 56 pM (Ardati et al., Mol. Pharmacol. 51, pp. 816-824), and by a high selectivity for the ORL1 receptor. The ORL1 receptor is homologous to the &mgr;, &kgr; and &dgr; opioid receptors, and the amino acid sequence of the nociceptin/orphanin FQ peptide has a strong similarity to those of the known opioid peptides. The activation of the receptor induced by nociceptin/orphanin FQ leads via the coupling with G
i/o
proteins to an inhibition of adenylate cyclase (Meunier et al., Nature 377, 1995, pp. 532-535). Also, at the cellular level there are functional similarities between the &mgr;, &kgr; and &dgr; opioid receptors and the ORL1 receptor as regards the activation of the potassium channel (Matthes et al., Mo. Pharmacol. 50, 1996, pp. 447-450; Vaughan et al., Br. J. Pharmacol. 117, 1996, pp. 1609-1611) and the inhibition of the L, N and P/Q type calcium channels (Conner et al., Br. J. Pharmacol. 118, 1996, pp. 205-207; Knoflach et al., J. Neuroscience 16, 1996, pp. 6657-6664).
The nociceptin/orphanin FQ peptide exhibits after intercerebroventricular application a pronociceptive and hyperalgesic activity in various animal models (Reinscheid et al., Science 270, 1995, pp. 792-794; Hara et al., Br. J. Pharmacol. 121, 1997, pp. 401-408). These results may be explained as inhibition of stress-induced analgesia (Mogil et al., Neurosci. Letters 214, 1996, pp. 131-134, as well as Neuroscience 75, 1996, pp. 333-337). In this connection an anxiolytic activity of the nociceptin/orphanin FQ peptide was also detected (Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858).
On the other hand an antinociceptive effect of nociceptin/orphanin FQ, in particular after intrathecal application, was also found in various animal models. Nociceptin/orphanin FQ inhibits the activity of kainate-stimulated or glutamate-stimulated posterior root ganglioneurons (Shu et al., Neuropeptides, 32, 1998, 567-571) or glutamate-stimulated spinal cord neurons (Faber et al., Br. J. Pharmacol., 119, 1996, pp. 189-190); nociceptin/orphanin FQ has an anti- nociceptive action in the tail-flick test in mice (King et al., Neurosci. Lett., 223, 1997, 113-116), in the flexor-reflex model in rats (Xu et al., NeuroReport, 7, 1996, 2092-2094) and in the formalin test in rats (Yamamoto et al., Neuroscience, 81, 1997, pp. 249-254). An antinociceptive effect of nociceptin/orphanin FQ was also detected in neuropathic pain models (Yamamoto and Nozaki-Taguchi, Anesthesiology, 87, 1997), which is all the more interesting in that the efficacy of nociceptin/orphanin FQ increases after axotomy of spinal nerves. This is in contrast to conventional opioids, whose efficacy decreases under these conditions (Abdulla and Smith, J. Neurosci., 18, 1998, pp. 9685-9694).
The nociceptin/orphanin FQ ligand ORL1 receptor system is also involved in the regulation of further physiological and pathophysiological processes. These include, inter alia, learning and the formation of memory (Sandin et al., European. J. Neurosci., 9, 1997, pp. 194-197; Manabe et al., Nature, 394, 1997, pp. 577-581), auditory perception (Nishi et al., EMBO J., 16, 1997, pp. 1858-1864), food intake (Pomonis et al., NeuroReport, 8, 1996, pp. 369-371), blood pressure regulation (Gumusel et al., Life Sci., 60, 1997, pp. 141-145; Campion and Kadowitz, Biochem. Biophys. Res. Comm., 234, 1997, pp. 309-312), epilepsy (Gutierrez et al., Abstract 536.18, Society for Neuroscience, Vol. 24, 28
th
Ann. Meeting, Los Angeles, Nov. 7-12, 1998) and diuresis (Kapista et al., Life Sciences, 60, 1997, PL 15-21).
Morphinan derivatives as well as processes for their production are known from WO 98/22467, WO 95/31463 and WO 95/31464. These compounds are described as &dgr;-selective opioid agonists and opioid antagonists for the treatment of conditions such as for example shock, constipation, mental disorders, eating disorders, injury to the central nervous system, alcoholism and immune function disorders.
The object of the present invention was to provide medicaments that act on the nociceptin/orphanin FQ ligand ORL1 receptor system and are thus suitable for treating neuropathic pain and/or anxiolysis and/or depression and/or diuresis and/or urinary incontinence and/or hypotension and or hypertension and/or senile dementia and/or Alzheimer's disease and/or general cognitive dysfunctions and/or tinnitus and/or impaired hearing and/or epilepsy and/or obesity and/or cachexia.
DETAILED DESCRIPTION OF THE INVENTION
It has now surprisingly been found that morphinan derivatives of the following general formula I exert an influence on the control of various physiological and pathophysiological processes in which the nociceptin/ orphanin FQ ligand ORL1 receptor system is involved. The aforementioned processes include, inter alia, the sensation of neuropathic pain, anxiety behavior, learning and memory formation, blood pressure regulation, hearing, food intake, epilepsy and diuresis.
The present invention accordingly provides for the use of morphinan derivatives of the general formula I
wherein
R
1
denotes H, a C
1-4
alkyl radical or a C
2-4
alkenyl radical,
R
2
denotes H, a C
1-18
alkyl radical, preferably a C
1-10
alkyl radical, a C
2-18
alkenyl radical, preferably a C
2-10
alkenyl radical, a heterocyclyl radical or an aryl radical,
R
3
denotes a C
1-18
alkyl radical, preferably a C
1-10
alkyl radical, a C
2-18
alkenyl radical, preferably a C
2-10
alkenyl radical, a C
3-7
cycloalkyl, aryl or heterocyclyl radical bound via a C
1-4
alkylene group, or a C
3-7
cycloalkyl, aryl or heterocyclyl radical bound via a C
2-4
alkenylene group,
R
4
denotes H, a C
1-18
alkyl radical, preferably a C
1-10
alkyl radical, a C
2-18
alkenyl radical, preferably a C
2-10
alkenyl radical, a C
3-7
cycloalkyl or aryl radical bound via a C
1-4
alkylene group, or a C
3-7
cycloalkyl or aryl radical bound via a C
2-4
alkenylene group, and
X denotes O or NR
5
where
R
5
denotes H, a C
1-18
alkyl radical, preferably a C
1-10
alkyl radical, a C
2-18
alkenyl radical, preferably a C
2-10
alkenyl radical, a C
3-7
cycloalkyl, aryl or heterocyclyl radical bound via a C
1-4
alkylene group, or a C
3-7
cycloalkyl, aryl or heterocyclyl radical bound via a C
2-4
alkenylene group,
and/or their enantiomers, diastereomers, or physiologically compatible salts, as regulators for the nociceptin/orphanin FQ ligand ORL1 receptor system.
The term alkyl radicals also includes hydrocarbons at least singly substituted preferably by halogen, particularly preferably by fluorine. If these contain one or more substituents, then the latter may be identical or different. Preferably the alkyl radicals are methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, heptyl, nonyl or decanyl.
The term alkenyl radicals also includes hydrocarbons that contain at least one double bond, and may be at least singly substituted, preferably by halogen, particularly preferably by fluorine. If the alkenyl radical contains more than one substituent, then these may be identical or different. Preferably the alkenyl radicals are 2-propenyl, 2-butenyl, 1-methyl-2-propenyl or 2-methyl-2-propenyl.
The term aryl radical also includes phenyl or naphthyl radicals at least singl
Buschmann Helmut
Krueger Thomas
Reiss-Mueller Elke
Strassburger Wolfgang
Wnendt Stephan
Crowell & Moring LLP
Gruenenthal GmbH
Henley III Raymond
LandOfFree
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